Bacterial infection and neutropenia during peginterferon plus ribavirin combination therapy in patients with chronic hepatitis C with and without baseline neutropenia in clinical practice

Background  Peginterferon-α–based therapy frequently leads to neutropenia. It remains unclear whether neutropenia is associated with bacterial infection in chronic hepatitis C (CHC).
Aim  To evaluate the risk of bacterial infection and neutropenia in patients with CHC treated with peginterferon-α/ribavirin.
Methods  In all, 207 patients with CHC with (group A, n  =   30) and without (group B, n  =   177) baseline neutropenia were treated with peginterferon-α/ribavirin.
Results  Group A had significantly higher rates of moderate (<750 cells/μL) and severe (<500 cells/μL) neutropenia than group B (70.0% and 26.7% vs. 20.3% and 8.5% respectively, both P  <   0.0001). The sustained virological response rate was similar between patients with and without neutropenia, at baseline or during treatment. Bacterial infection occurred in 4.3% of patients. Group A and patients with lower baseline neutrophil counts had substantially higher rates of bacterial infection. Patients with cirrhosis had significantly higher rates of infection during combination therapy than those without cirrhosis (15%, 3 of 20 vs. 3.2%, 6 of 187, P  =   0.045). Nadir neutrophil counts were not correlated to infection episodes.
Conclusions  Bacterial infection during peginterferon-based therapy for CHC was associated with comorbidity of cirrhosis, but not with neutropenia, whether at baseline or during treatment. Neutropenic CHC patients might be treated safely with close monitoring.     

Sustained virological responses following standard anti-viral therapy in decompensated HCV-infected cirrhotic patients

Background  Little data is available about predictors of sustained virological response (SVR) during anti-viral therapy of patients with decompensated HCV cirrhosis.
Aims  To determine whether rapid and early virological responses (RVR and EVR) could predict SVR and help optimize treatment in these patients.
Methods  A total of 94 cirrhotics underwent treatment with peg-interferon alfa-2b (1.5 μg/kg weekly) and ribavirin (800/1200 mg daily) for 48 or 24 weeks for genotypes 1/4 or genotypes 2/3, respectively.
Results  Overall, SVR was achieved in 33 patients (35.1%), 16% with genotype 1/4 and 56.8% with genotype 2/3 ( P  < 0.01). At treatment week 4, 34 patients had undetectable HCV-RNA, 10 with genotype 1/4 and 24 with genotype 2/3. Of RVR patients, 24 achieved SVR (70.5%), 6 and 18 with genotypes 1 and non-1. At the multivariate analysis, only EVR, genotypes 2 and 3, and adherence to full course and dosage of therapy retained their independent predictive power, with corresponding ORs of 25.5 (95% CI 3.0–217.3), 4.2 (95% CI 1.2–15.3) and 9.1 (95% CI 2.2–38.0), respectively.
Conclusion  In decompensated cirrhotic patients, anti-viral therapy with current regimens is feasible and associated with an overall SVR rate of 35.1%. Treatment ought to be pursued among patients who attain an EVR, and maintain a full course and dosage of therapy.     

Apolipoprotein B-associated cholesterol is a determinant of treatment outcome in patients with chronic hepatitis C virus infection receiving anti-viral agents interferon-alpha and ribavirin

Background  Hepatitis C virus (HCV) co-opts very-low-density lipoprotein (VLDL) pathways for replication, secretion and entry into hepatocytes and associates with apolipoprotein B (apoB) in plasma. Each VLDL contains apoB-100 and variable amounts of apolipoproteins E and C, cholesterol and triglycerides.
Aim  To determine whether baseline lipid levels predicted treatment outcome.
Methods  Retrospective analysis was performed of 250 chronic hepatitis C (CHC) patients who had received anti-viral agents interferon-alpha and ribavirin; 165 had a sustained virological response (SVR). Pre- and post-treatment nonfasting lipid profiles were measured and non-high-density lipoprotein (non-HDL) cholesterol (i.e. apoB-associated) was calculated. Binary logistic regression analysis assessed factors independently associated with treatment outcome.
Results  There was an independent association between higher apoB-associated cholesterol (non-HDL-C) and increased odds of SVR (odds ratio 2.09, P  = 0.042). In multivariate analysis, non-HDL-C was significantly lower in HCV genotype 3 (g3) than genotype 1 ( P  = 0.007); this was reversible upon eradication of HCVg3 (pre-treatment non-HDL-C = 2.8 mmol/L, SVR = 3.6 mmol/L, P  < 0.001).
Conclusions  Higher apoB-associated cholesterol is positively associated with treatment outcome in CHC patients receiving anti-viral therapy, possibly due to competition between apoB-containing lipoproteins and infectious low-density HCV lipo-viral particles for hepatocyte entry via shared lipoprotein receptors.     

Efficacy and safety of antiviral therapy in patients with Crohn's disease and chronic hepatitis C

Background  Efficacy and safety of antiviral combination therapy in patients with Crohn's disease (CD) and chronic hepatitis C (CHC) is presently not established and consequently CHC is rarely treated in CD patients.
Aim  To analyse the efficacy and tolerability of antiviral interferon/ribavirin therapy in patients with CHC and CD.
Methods  Eleven HCV-infected CD patients received either 3 × 1.5 μg/kg/week interferon-α-2b or 180 μg/week peginterferon-α-2a (PEGASYS; Roche, Basel, Switzerland) as monotherapy ( n  = 1) or in combination with 800–1200 mg/day ribavirin (COPEGUS; Roche) ( n  = 10) for 24–54 weeks according to HCV-genotype and initial response respectively. Eight patients were under CD-specific therapy.
Results  Five (46%) patients (HCV-1: n  = 3; HCV-2: n  = 0; HCV-3: n  = 1; unknown: n  = 1) achieved a sustained virological response, three (27%) patients relapsed, three (27%) were nonresponders (all GT 1b). At baseline, the Harvey–Bradshaw Index was 0 (0–8) [median (range)], increased on antiviral therapy to 4 (1–15) ( P  = 0.005) and decreased to baseline level 0 (0–6) after 6-month follow-up.
Conclusions  This preliminary experience demonstrates that treatment of CHC in patients with CD is comparable to the treatment of CHC in those without CD. However, gastrointestinal symptoms may be temporarily exacerbated and haemopoietic growth factors may be required.     

Serum HCV RNA levels and HCV genotype do not affect insulin resistance in nondiabetic patients with chronic hepatitis C: a multicentre study

Background  Chronic hepatitis C (CHC) induces insulin resistance (IR) and subsequently diabetes.
Aim  To examine viral, metabolic and histological predictors of IR in 275 CHC patients to test the hypothesis that IR differs among HCV genotypes and that viral replication directly affects IR.
Methods  We studied 275 nondiabetic treatment-naïve CHC patients. Histological lesions were evaluated according to Ishak. IR was assessed using homeostasis model assessment for insulin resistance (HOMA-IR).
Results  HOMA > 3.0 was found in 37% of patients, independently associated with higher BMI and GGT. In genotype non-3 patients, HOMA > 3.0 was associated with higher BMI and GGT values, while no significant association was noted in genotype 3 patients. In non-obese patients with minimal fibrosis, HOMA > 3.0 was found in 20% of cases without significant differences among genotypes. No association between HOMA > 3.0 and HCV-RNA levels was found. Severe fibrosis (stage 5–6) related to older age (OR:1.048), HOMA-IR (OR:1.177), necroinflammation (OR: 2.990) and higher ALT (OR: 1.009) and GGT (OR:1.006).
Conclusions  IR develops at early stages of CHC without significant differences among genotypes. It is more frequent in obese patients with steatosis and contributes to fibrosis progression. However, IR does not seem to be associated with viraemia and therefore its exact pathogenetic mechanism in CHC remains elusive.     

Longitudinal effects of hepatitis C virus treatment on hepatic mitochondrial dysfunction assessed by C-methionine breath test

Background  Hepatitis C virus (HCV) infection is characterized by remarkable levels of oxidative stress induced by virus interactions with hepatic mitochondria.
Aim  To examine hepatic mitochondrial function in HCV-infected patients assessed by a non-invasive ¹³C-methionine breath test (MeBT) and to explore longitudinal effects of antiviral treatment.
Methods  Twenty-one patients with chronic hepatitis C undergoing antiviral treatment with pegIFNα and ribavirin and 20 healthy controls were studied. MeBT was performed at baseline, week 12, end-of-treatment and after 24 weeks of follow-up in all patients with early virological response ( n  = 15).
Results  Twelve patients achieved sustained virological response (SVR); three patients relapsed for HCV-RNA replication. Cumulative percentage ¹³C-exhalation (cPDR_1.5h) was significantly decreased in HCV-infected individuals compared to controls irrespective of genotype and fibrosis stage ( P  < 0.001). Antiviral treatment induced a further decay in cPDR_1.5h ( P  < 0.01). After treatment cessation, ¹³C-exhalation returned at least to baseline values in all patients. SVR was even associated with a mean cPDR_1.5h increase of 70% compared to baseline.
Conclusions  Hepatitis C virus infection and antiviral treatment synergistically impair hepatic mitochondrial function, which may return to normal after sustained virus elimination. MeBT may be a valuable diagnostic instrument for monitoring hepatic mitochondrial function in particular in patients with mitochondrial comorbidities.     

Increased plasma ghrelin following infliximab in Crohn's disease

Background  Ghrelin, a potent orexigenic peptide produced by the stomach, may be affected by circulating inflammatory mediators.
Aim  To assess the effect of an anti-TNFα antibody on ghrelin in patients with Crohn's disease (CD).
Methods  Fifteen patients with Crohn's receiving infliximab were studied before and 1 week after infusion. Following an overnight fast, blood was sampled before a meal and then every 20 min for 2 h. Total ghrelin and CRP were measured using ELISA. Acylated ghrelin and TNFα, IFNγ, IL-1β and IL-6 were measured with bioplex. Harvey Bradshaw Activity Index was assessed.
Results  Median (95% CI) 2-h integrated plasma total ghrelin increased from 162 (99–311) before infliximab to 200 (128–387) pg/mL h, ( P  = 0.02) after. Following infliximab, 20 min postmeal, median acylated ghrelin decreased from 50.3 (24–64) to 38.6 (26–82) pg/mL, ( P  = 0.04) thus reverting to a traditional meal related ghrelin curve. Median (range) disease activity decreased from 5 (2–28) before to 3 (0–22), ( P  = 0.0001) and Median (95% CI) TNFα decreased from 2.8 (1.89–4.48) to 1.31 (0.73–2.06) pg/mL ( P  = 0.002).
Conclusions  Infliximab increases circulating total ghrelin by 25% in CD and restores the postprandial response of acylated ghrelin to food intake. Acylated and de-sacyl ghrelin remain unchanged, suggesting that an alternate isoform could be affected by infliximab.     

Quantitative tests of liver function measure hepatic improvement after sustained virological response: results from the HALT-C trial

Backgroud  The impact of virologic response on hepatic function has not been previously defined.
Aim  To determine the relationships of quantitative liver function tests (QLFTs) with virological responses to peginterferon (PEG) ± ribavirin (RBV) in patients with chronic hepatitis C and to use serial QLFTs to define the spectrum of hepatic improvement after sustained virological response (SVR).
Methods  Participants ( n  = 232) were enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial, had failed prior therapy, had bridging fibrosis or cirrhosis and were retreated with PEG/RBV. All 232 patients had baseline QLFTs; 24 patients with SVR and 68 nonresponders had serial QLFTs. Lidocaine, [24-¹³C]cholate, galactose and ^99mTc-sulfur colloid were administered intravenously; [2,2,4,2-²H]cholate, [1-¹³C]methionine, caffeine and antipyrine were administered orally. Clearances ( Cl ), breath ¹³CO₂, monoethylglycylxylidide (MEGX), perfused hepatic mass (PHM) and liver volume were measured.
Results  Rates of SVR were 18–26% in patients with good function by QLFTs, but ≤6% in patients with poor function. Hepatic metabolism, measured by caffeine k _elim ( P  = 0.02), antipyrine k _elim ( P  = 0.05) and antipyrine Cl ( P  = 0.02) and the portal circulation, measured by cholate Cl _oral ( P  = 0.0002) and cholate shunt ( P  = 0.0003) and PHM ( P  = 0.03) improved after SVR.
Conclusion  Hepatic dysfunction impairs the virological response to PEG/RBV. SVR improves hepatic metabolism, the portal circulation and PHM.     

Meta-analysis: the outcome of anti-viral therapy in HCV genotype 2 and genotype 3 infected patients with chronic hepatitis

Background  Anti-viral therapy seems more successful in HCV genotype 2 than genotype 3-infected patients.
Aim  To report sustained virological response (SVR) rates for HCV-2 and HCV-3 infection.
Methods  Meta-analyses were carried out on SVR data on 2275 patients treated for 24 weeks in eight individual trials and on 968 patients with rapid virological response (RVR) treated for 12–16 weeks or 24 weeks in four studies.
Results  After 24 weeks of therapy, SVR rates were 74% and 68%, respectively, for HCV-2 and HCV-3 genotype patients. Among high viraemics, SVR rate in HCV-2 infection (75%) differed from the 58% value in HCV-3 infection. Among low viraemic patients, respective rates were 79% and 75%. In RVR patients treated for 12–16 or 24 weeks, SVR rates in HCV-2 infection were 83% and 84%, respectively, and in HCV-3 infection 84% and 86%. In patients without RVR treated for 24 weeks, SVR was higher in HCV-2, with a 17.8% weighted difference.
Conclusions  Twenty-four weeks of therapy should remain standard duration for HCV-2 and low viraemic HCV-3 patients. In RVR patients, HCV-3 patients respond to short-treatment as well as HCV-2 patients, irrespective of basal viraemia. Patients without RVR may need longer treatment than the recommended 24 weeks.     

Impact of ribavirin plasma level on sustained virological response in patients treated with pegylated interferon and ribavirin for chronic hepatitis C

Background  The main goal of therapy in hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). However, the impact of the pharmacological properties of ribavirin on the SVR has not been fully investigated.
Aim  To evaluate, through a prospective study, the association between ribavirin plasma level and SVR response in HCV patients treated with pegylated interferon (PEG-IFN) and ribavirin.
Patients and methods  Patients treated with PEG-IFN and ribavirin had plasmatic ribavirin dosage at weeks 4 and 12. SVR was evaluated 6 months after the end of treatment.
Results  At week 4, a strong correlation was found between HCV-RNA and C _min of ribavirin plasma level ( r  = −0.376, P  = 0.002) and AUC _0→12h of ribavirin plasma level ( r  = −0.277, P  = 0.018). At week 12, a strong correlation was found between HCV-RNA and C _min of ribavirin plasma level ( r  = −0.384, P  < 0.0001) and AUC _0→12h of ribavirin plasma level ( r  = −0.257, P  = 0.002). In genotype 1 patients, AUC _0→12h ribavirin and C _min were significantly correlated with negative HCV-RNA at week 12 and SVR. In the multiple logistic regression model, the only factor independently associated with SVR in genotype 1 patients was negative HCV-RNA at week 12.
Conclusion  C_min of ribavirin at weeks 4 and 12 was significantly higher in sustained virological responders compared with relapser or nonresponder patients. However, in genotype 1 patients, plasma ribavirin level at weeks 4 and 2 was not associated with SVR.     

Clinical trial: extended treatment duration of peginterferon-alpha2b plus ribavirin for 72 and 96 weeks in hepatitis C genotype 1-infected late responders

Background  The benefits of prolonging peginterferon and ribavirin after 48 weeks of treatment to maximize sustained virological responses (SVR) in hepatitis C virus (HCV) genotype 1-infected patients remain to be understood.
Aim  To investigate whether extended treatment longer than 72 weeks may be superior to 72-week treatment.
Methods  A total of 120 treatment-naïve or retreated patients with HCV genotype 1 were treated with peginterferon-alpha-2b (1.5 μg/kg/week) plus weight-based ribavirin. We had 34 late responders, in whom HCV RNA first became undetectable at week 12–48, and randomized them into three groups receiving standard-dose peginterferon-alpha-2b plus low-dose ribavirin (200 mg/day) for extended 24 weeks (group A), receiving low-dose peginterferon-alpha-2b (0.75 μg/kg/week) plus low-dose ribavirin for extended 48 weeks (group B) or no extended treatment (group C), and evaluated the outcome according to their virological response.
Results  Multivariate analysis showed that the treatment for 96 weeks was identified as a significant, independent factor associated with SVR in HCV genotype 1-infected late responders in comparison with group A [odds ratio (OR), 10.002; P  =   0.080] and group C (OR, 17.748; P  =   0.025).
Conclusion  Extending the treatment duration from 48 weeks to 96 weeks improves SVR rates in genotype 1-infected patients with late virological response to peginterferon-alpha-2b and ribavirin.     

Clinical trial: peg-interferon alfa-2b and ribavirin for the treatment of genotype-1 hepatitis C recurrence after liver transplantation

Background  Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is difficult with low response rates.
Aim  To assess the safety and efficacy of pegylated-interferon (PEG-IFN) alfa-2b + ribavirin (RBV) in patients with post-LT recurrent genotype-1 HCV and to establish stopping rules according to response.
Methods  Fifty-three patients with post-LT HCV recurrence were enrolled. Patients received PEG-IFN alfa-2b 1.0 μ/kg/week plus RBV 8–10 mg/kg/day for 24 weeks. Those with 'early virological response at week 24' (EVR24) continued treatment for 24 weeks (group A). Patients without EVR24 were randomized to continue (group B) or to discontinue (group C).
Results  Overall sustained virological response (SVR) was 26% (14/53). Alanine aminotransferase, rapid virological response, EVR12, EVR24, undetectable serum HCV-RNA at weeks 12 (cEVR12) and 24 (cEVR24) were related to SVR. cEVR12 and cEVR24 (OR: 14.7; 95% CI: 2.02–106.4) were independent predictors of SVR. All patients with SVR, had cEVR12. No patient in groups B and C achieved end-of-treatment response. One patient in group B had SVR.
Conclusions  Pegylated-interferon alfa-2b was effective in one of four of patients with HCV genotype 1 after LT. Treatment should be discontinued in patients with no virological response at week 12. Further studies are needed to evaluate whether a longer treatment period may be beneficial in patients with ≥2 log₁₀ drop in HCV-RNA at week 24.     

TMC435 for the treatment of chronic hepatitis C

INTRODUCTION: Chronic hepatitis C (CHC) virus infection affects more than 170 million people globally. The aim of treatment of CHC is to effect sustained elimination of the virus (a sustained virological response, SVR). Prior to the development of direct-acting antiviral (DAA) agents, the standard of care (SOC) for CHC comprised combined treatment with pegylated interferon (PegIFN) and ribavirin (RBV). AREAS COVERED: TMC435 (Tibotec pharmaceuticals) is a macrocyclic non-covalent NS3/NS4A protease inhibitor (DAA) that is currently in Phase III clinical development. TMC435 is being developed in treatment regimens both with and without PegIFN and RBV. In Phase IIb clinical trials, the addition of TMC435 to current SOC significantly increased the SVR rate in both treatment-naive and experienced patients with CHC. It differs, however, from the other first-generation protease inhibitors in that it is administered once daily, has a different tolerability and resistance profile and has activity against CHC genotypes 1 - 6 with the exception of genotype 3. Furthermore, the addition of TMC435 to PegIFN/RBV appears to be able to significantly shorten treatment duration in the majority of patients. This article will review the pharmacology, pharmacodynamics, safety and efficacy of TMC435 by evaluating the preclinical and clinical studies to date. ExPERT OPINION: TMC435 is a 'second-wave' protease inhibitor that has the potential to play a pivotal role in the next phase of CHC treatment. The forthcoming results of Phase III trials involving TMC435 are awaited with interest.     

Presence of HCV-RNA after ultracentrifugation of serum samples during the follow-up of chronic hepatitis C patients with a sustained virological response may predict reactivation of hepatitis C virus infection

Background  Concentration of viral particles by ultracentrifugation of serum prior to PCR allows detection of hepatitis C virus (HCV) RNA in patients with undetectable viral RNA by conventional PCR assays.
Aim  To analyse if HCV-RNA is detected after serum ultracentrifugation in chronic hepatitis C patients with a sustained virological response to antiviral therapy (defined as serum HCV-RNA negativity by conventional assays 6 months after the end of therapy).
Methods  HCV-RNA was tested using real-time PCR in ultracentrifuged sera collected during the post-treatment follow-up (mean: 42 ± 27 months) in 57 sustained virological responders (SVR).
Results  After serum ultracentrifugation, HCV-RNA was detected on at least one occasion during the follow-up in 29/57 (51%) SVR. Thirteen (23%) of these 57 SVR suffered a reactivation 18 ± 8 months after the end of therapy (reappearance of serum HCV-RNA detectable by conventional assays). Among reactivated patients, 11/13 (85%) had HCV-RNA in ultracentrifuged serum samples (detectable 10 ± 5 months before reactivation), while HCV-RNA was positive after ultracentrifugation in 18/44 (41%) long-term SVR ( P  = 0.01). Persistence of detectable HCV-RNA after serum ultracentrifugation was associated with reactivation ( P  = 0.001).
Conclusions  Serum ultracentrifugation prior to PCR allows detection of HCV-RNA in SVR and its persistence may predict late reactivation.     

Clinical trial: exposure to ribavirin predicts EVR and SVR in patients with HCV genotype 1 infection treated with peginterferon alpha-2a plus ribavirin

Background  The impact of reduced drug exposure on outcomes in patients with chronic hepatitis C has not been determined in routine clinical practice.
Aim  To examine the impact of exposure to peginterferon alfa-2a and ribavirin on early virological response (EVR) and sustained virological response (SVR) in treatment-naïve patients with HCV genotype 1 infection enrolled in a large expanded access programme.
Methods  Eight hundred and ninety-one patients treated for 48 weeks with an initial ribavirin dose of 800 or 1000/1200 mg/day were evaluated. Ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg) and peginterferon alfa-2a 180 μg/week were considered optimal. The impact of reduced drug exposure (expressed as a percentage of optimal) on EVR and SVR was evaluated.
Results  Mean ribavirin exposure in week 0–12 was 70% and 96% in patients assigned to ribavirin 800 and 1000/1200 mg/day, respectively. EVR and SVR rates were lower in patients assigned to ribavirin 800 than 1000/1200 mg/day (EVR, 75% vs. 84%, respectively, P  < 0.001; SVR, 45% vs. 54%, respectively, P  = 0.011). Furthermore, there was a strong correlation between achievement of EVR and SVR and ribavirin dose over the first 12 weeks expressed either as absolute dose or proportion of optimal dose received ( P  < 0.001 for both).
Conclusions  Ribavirin exposure to week 12 is significantly associated with EVR and SVR in genotype 1 patients. Maintenance of an optimal ribavirin dose is the most important modifiable factor during combination therapy for chronic hepatitis C.     

Transient elastography to assess hepatic fibrosis in primary biliary cirrhosis

Background  Liver stiffness measurements may have potential for detecting and monitoring hepatic fibrosis in chronic liver disease.
Aim  To study the detection, quantification and progression of hepatic fibrosis in primary biliary cirrhosis by liver stiffness measurements.
Methods  Liver stiffness measurements were generated in 80 patients with primary biliary cirrhosis by applying transient elastography; however, as there were 55 with liver biopsy, histological stage (METAVIR) and liver stiffness measurements were compared only in these 55 patients. The efficiency of liver stiffness measurements in predicting stage of fibrosis was determined from the area under receiver operating characteristics curve analysis.
Results  Of the 80 patients included, 91, 4% were women and their mean age was 56 ± 12 (s.d.) years. A significant correlation was found ( P  < 0.05) between histological fibrosis stage (METAVIR) and liver stiffness measurements. The values obtained from area under receiver operating characteristic curve analysis of liver stiffness measurement data were 0.89 for F  > 2 and 0.96 for F  = 4. Liver stiffness measurements were 9.0 ± 5.3 and 7.9 ± 6.0 kPa for patients followed up more than 5 years and less than 5 years, respectively ( P  > 0.05).
Conclusions  In patients with primary biliary cirrhosis, median values of liver stiffness measurements correlated with histological severity of hepatic fibrosis. Liver stiffness measurements appear to be promising for liver fibrosis detection and quantification, as well as monitoring its progression, in patients with primary biliary cirrhosis. The progression rate of hepatic fibrosis in our primary biliary cirrhosis patients appears to be slow.     

Insulin resistance is a major determinant of liver stiffness in nondiabetic patients with HCV genotype 1 chronic hepatitis

Background  In patients with chronic hepatitis C (CHC), liver stiffness measurement (LSM) by transient elastography (TE), is closely related to the stage of fibrosis, but may be affected by necroinflammation. Other factors, such as insulin resistance (IR), might influence the performance of LSM.
Aims  To evaluate in a cohort of nondiabetic patients with genotype 1 CHC, whether IR and other anthropometric, biochemical, metabolic and histological factors contribute to LSM and to identify the best cut-off values of LSM for predicting different stages of fibrosis.
Methods  Nondiabetic patients with genotype 1 CHC ( n  = 156) were evaluated by liver biopsy (Metavir score), anthropometric, biochemical and metabolic features including IR. Furthermore, all subjects underwent LSM by TE.
Results  Severe fibrosis (F3–F4) was associated with LSM (OR 1.291; 95%CI 1.106–1.508). LSM was also independently correlated with low platelets ( P  =   0.03), high γGT ( P  <   0.001) and high HOMA ( P  =   0.004) levels. A stiffness value ≥8 KPa was identified as the best cut-off for predicting severe fibrosis ( AUC 0.870); yet this cut-off still failed to rule out F3–F4 fibrosis in 22.7% of patients (false-negative rate) or rule in F3–F4 in 19.6% (false-positive rate). Platelets <200 × 10³/mmc and a HOMA of >2.7 were the major determinants of these diagnostic errors in predicting severe fibrosis.
Conclusions  In nondiabetic patients with genotype 1 CHC, insulin resistance, γGT and platelet levels contribute to LSM independently of liver fibrosis. The identification of these three factors contributes to a more correct interpretation of LSM.     

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.     

Clinical trial: a randomized trial of pegylated-interferon-α-2a plus ribavirin with or without amantadine in treatment-naïve or relapsing chronic hepatitis C patients

Background  The combination therapy of pegylated-interferon-α2a plus ribavirin is considered as the standard of care for patients with chronic hepatitis C. A sustained viral response is obtained in 40–50% of naïve patients with genotype 1 and in around 80% of naïve patients with genotype 2 or 3.
Aim  To assess whether amantadine, added to the conventional combination therapy, could improve the treatment efficacy.
Methods  In all, 630 patients (intent-to-treat population) with chronic hepatitis C were randomized into two groups: 316 patients (treatment group) received pegylated-interferon-α2a (180 μg once weekly) plus ribavirin (1000–1200 mg/daily) with amantadine (200 mg/daily); 314 patients (control group) received pegylated-interferon-α2a (180 μg once weekly) plus ribavirin (1000–1200 mg/daily) without amantadine. The duration of the treatment was 48 weeks for genotypes 1, 4, 5 and 6, and 24 weeks for genotypes 2 and 3.
Results  There was no statistically significant difference between treatments groups for any of the variables tested for. Subgroups of patients likely to take advantage of the addition of amantadine were not identified.
Conclusions  This large study definitely excludes the role of amantadine in addition of conventional combination therapy in the treatment of chronic hepatitis C patients.     

慢性丙型肝炎合并肝硬化的抗病毒方案

摘 要 经过目前标准的治疗方案治疗后,慢性丙型肝炎（丙肝）合并肝硬化的患者疗效不佳。随着治疗丙肝新药越来越多,许多新的治疗慢性丙肝合并肝硬化的抗病毒方案出现了。由于第一代蛋白酶抑制药博赛匹韦、特拉匹韦的不良反应较大,因此用于丙肝合并肝硬化患者的治疗需要谨慎。其他治疗丙肝的新药辛姆匹韦、索非布韦、来第帕韦对于丙肝合并代偿性硬肝化患者有疗效,但是有合并症患者的病毒应答（SVR）低于没有合并症的患者。因此,今后需要优化这些药物组合的治疗方案,以此缩小持续性的病毒应答的差距。