Telaprevir- and boceprevir-based tritherapies in real practice for F3-F4 pretreated hepatitis C virus patients.

AIM: To assess, in a routine practice setting, the sustained virologic response (SVR) to telaprevir (TPV) or boceprevir (BOC) in hepatitis C virus (HCV) null-responders or relapsers with severe liver fibrosis. METHODS: One hundred twenty-five patients were treated prospectively for 48 wk with TPV or BOC + pegylated-interferon (peg-INF) α2a + ribavirin (PR) according to standard treatment schedules without randomization. These patients were treated in routine practice settings in 10 public or private health care centers, and the data were prospectively collected. Only patients with severe liver fibrosis (Metavir scores of F3 or F4 upon liver biopsy or liver stiffness assessed by elastography), genotype 1 HCV and who were null-responders or relapsers to prior PR combination therapy were included in this study. RESULTS: The Metavir fibrosis scores were F3 in 35 (28%) and F4 in 90 (72%) of the patients. In total, 62.9% of the patients were null-responders and 37.1% relapsers to the previous PR therapy. The overall SVR rate at 24 wk post-treatment withdrawal was 59.8%. The SVR was 65.9% in the TPV group and 44.1% in the BOC group. Independent predictive factors of an SVR included a response to previous treatment, relapsers vs null-responders [OR = 3.9; (1.4, 10.6), P = 0.0084], a rapid virological response (RVR) [OR 6.9 (2.6, 18.2), P = 0.001] and liver stiffness lower than 21.3 kPa [OR = 8.2 (2.3, 29.5), P = 0.001]. During treatment, 63 patients (50.8%) had at least one severe adverse event (SAE) of grade 3 or 4. A multivariate analysis identified two factors associated with SAEs: female gender [OR = 2.4 (1.1, 5.6), P = 0.037] and a platelet count below 150 × 10(3)/ mm(3) [OR = 5.3 (2.3, 12.4), P ≤ 0.001]. CONCLUSION: More than half of these difficult-to-treat patients achieved an SVR and had SAEs in an actual practice setting. The SVR rate was influenced by the response to previous PR treatment, the RVR and liver stiffness.

Non-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study.

BACKGROUND: The efficacy of a maintenance therapy in non-responder patients with chronic hepatitis C has been essentially evaluated by histological semiquantitative scores. AIM: The aim was to evaluate the efficiency of 2 years of treatment with peginterferon alpha-2a vs alpha-tocopherol in these patients by histology, morphometry and blood markers of fibrosis. METHOD: Hundred and five HCV patients with a Metavir fibrosis score > or = 2 were randomized to receive peginterferon alpha-2a 180 microg/week (PEG) (n=55) or alpha-tocopherol (TOCO) 1000 mg/day (n=50) for 96 weeks. The primary endpoint was improvement or stabilization of the Metavir fibrosis score by biopsy performed at week 96. Secondary endpoints included a quantitative assessment of fibrosis by morphometry and changes in blood markers of fibrosis. RESULTS: There was no difference at baseline between PEG and TOCO according to the metavir (83.3 vs 86.8%, P=0.751) stage. The median fibrosis rate, measured with morphometry was 2.72 and 2.86% at day 0, and 3.66 and 2.82% at week 96, in the PEG and TOCO groups (P=0.90) respectively. However, the percentage of patients with metavir activity grade improvement was significantly higher in the PEG group vs the TOCO group (52.8 vs 23.7%, P=0.016). Non-invasive markers analysis did not show any significant change in both groups. CONCLUSION: Long-term therapy with peginterferon alpha-2a did not reduce liver fibrosis degree assessed by morphometry and blood tests as compared with alpha-tocopherol. Blood tests could be useful to assess liver fibrosis changes in clinical trials.

Safety and efficacy of combination therapy with peginterferon alfa-2a (40kD) and ribavirin in the outpatient setting: prospective analysis of 197 patients with chronic hepatitis C viral infection.

OBJECTIVES: Combination therapy using peginterferon alfa-2a (40 kD) plus ribavirin achieves viral eradication in nearly 60% of patients with chronic hepatitis C viral infection. However, because of the numerous side effects, use of the combination regimen might be restricted for patients consulting private practitioners specialized in hepatogastroenterology. PATIENTS AND METHOD: Conducted in this specific context, this prospective clinical trial investigated the safety and efficacy of combination therapy in 197 patients. Therapy was given in compliance with the recommendations of the French consensus conference on hepatitis C treatment. RESULTS: Commonly reported adverse effects were noted in 90% of patients, most occurring during the first three months, with a stable prevalence thereafter and resolution after treatment end. The most frequent adverse events were asthenia (35 to 37.5% according to the treatment group pruritus (25 to 26.3%) and flu-like syndrome (19 to 21.7%). A depressive syndrome was reported in 20 to 21% of patients. Grade 4 neutropenia was exceptional and never led to severe infections. At intent-to-treat analysis, the rate of sustained virological response was 54.8% for the entire population. It was 71.1% for patients with genotypes 2 or 3 (mainly treated for 24 weeks) and 44.6% for patients with genotype 1 (all treated 48 weeks). CONCLUSION: The characteristic features of combination therapy observed in the context of private hepatogastroenterology consultations are similar to those observed in randomized clinical trials.

Effect of ribavirin in genotype 1 patients with hepatitis C responding to pegylated interferon alfa-2a plus ribavirin.

BACKGROUND & AIMS: Pegylated interferon alfa-ribavirin combination is the standard treatment for chronic hepatitis C, but the mechanisms by which ribavirin enhances the rate of sustained hepatitis C virus (HCV) eradication remain unknown. We aimed to investigate the role of ribavirin in HCV clearance during therapy and to evaluate the consequences of ribavirin discontinuation in patients infected with genotype 1 hepatitis C who cleared HCV RNA at week 24. METHODS: A total of 516 patients were treated with pegylated interferon alfa-2a, 180 microg/wk, plus ribavirin, 800 mg/day. Seventy percent were RNA negative at week 24. They were randomized to continue with the combination or receive pegylated interferon alone. RESULTS: Responders at week 24 who stopped ribavirin had a significantly higher rate of breakthroughs during, and relapses after, therapy (sustained virologic response, 52.8% vs 68.2%; P = .004), but their side-effect profile and quality of life tended to improve. Multiple logistic regression analysis in the pegylated interferon alfa monotherapy group allowed identification of responders at week 24 who could stop ribavirin without losing their chance of a sustained virologic response, based on baseline viral load and age. Forty-eight weeks of ribavirin may not be needed when HCV RNA is undetectable at week 2. CONCLUSIONS: We made 3 conclusions from this study. First, ribavirin primarily acts by sustaining the virologic response to pegylated interferon alfa; second, ribavirin must be administered for the full treatment duration in most genotype 1-infected patients who respond; third, baseline parameters may help identify patients who could discontinue ribavirin or reduce the dose without losing their chance of success.

[Assessment of quality of life in chronic hepatitis C: effect of treatment]. / Evaluation de la qualité de vie au cours de l'hépatite chronique C: influence du traitement.

OBJECTIVES: To study Quality of Life during chronic hepatitis C infection in patients recruited by hospital-based- or private hepatologists and to assess the effect of antiviral therapy. METHODS: A self-administered quality of life questionnaire (SF36) was proposed before, during, and 6 months after the end of treatment. The quality of life scales were assessed according to treatment response. RESULTS: 599 patients filled in the questionnaire before treatment and 168 patients 6 months after the end of treatment. After 6 months of therapy, patients with treatment response (n=54) showed increased scores in all SF-36 scales, this increase reaching more than 25% for "Role Physical", "General Health Perception" and "Vitality" scores. Non-responders (n=70) had an impairment of physical scores but a general improvement of Mental Health. CONCLUSION: This study confirms that sustained virological response is associated with an improved quality of life in hepatitis C patients. However, non-responders still have a positive "General Health Perception". Together with the development of new therapies, these observations could help to convince reluctant patients to be treated.

[Assessment of hepatitis C networks]. / Evaluation du fonctionnement des réseaux hépatites C.

AIMS: To assess the functioning of hepatitis networks. METHODOLOGY: A questionnaire was sent to all reference centers, to ten general hospitals and to twelve private hospitals working in hepatology. The main items included: participation and composition of networks, difficulties and positive or negative experiences, equal access to diagnostic and therapeutic means within the networks. Answers could be accompanied by personal remarks. RESULTS: The response rate was satisfactory: 75%, 70% and 100% respectively for the three groups. More than 80% of the questions were answered. Nearly all of the centers participate in a network. Two thirds of the reference centers have organized a therapeutic committee that includes private units and general hospitals. All groups actively participate in the networks. The positive experiences that were most often described were the success of training sessions especially in relation to equal access, and becoming acquainted with other participants. Most networks did not seem to be interested in screening. For reference centers the number of participating practitioners was too low. The main difficulty was felt to be overcentralization of the public hospital. Most networks are independent and meetings take place in the evening. Most responses were in favor of parity and equal access to diagnosis and therapeutic means within the networks. This only occurred in one third of the networks and if these measures were implemented it would increase network participation and effectiveness. Two thirds of the responses were also favourable to extending therapeutic trials to networks. CONCLUSION: Public and private hepatologists have similar opinions about hepatitis networks. Pooling of activities, responsibilities and means should be implemented and could improve participation in the networks.

Daily or three times a week interferon alfa-2b in combination with ribavirin or interferon alone for the treatment of patients with chronic hepatitis C.

BACKGROUND/AIMS: Data on hepatitis C virus (HCV) viral dynamics and on the effect of interferon in blocking virion production have suggested a rationale for daily administration of interferon in patients with chronic hepatitis C infection. We compared the efficacy and safety of daily interferon alfa-2b in combination with ribavirin with those of interferon alfa-2b three times a week alone or in combination with ribavirin. METHODS: We randomly assigned 321 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or in combination with ribavirin for 48 weeks or daily interferon alfa-2b (3 million units per day for 12 weeks then 3 million units three times per week for 24 weeks) and ribavirin (36 week treatment). RESULTS: The rate of sustained virologic response (defined as an undetectable serum HCV-RNA level 72 weeks after initiation of treatment) was higher in patients who received combination therapy with three times weekly interferon (51.7%) or daily interferon (46.1%) than in patients who received interferon alone (25%) (P=0.0001 and P=0.002, respectively). Independent predictive factors for sustained virologic response were combination therapy, weight, genotype and viral load. In conclusion, in patients with chronic hepatitis C, combination therapy with induction treatment (daily interferon for 12 weeks) and shorter duration of treatment was not different from combination therapy for 48 weeks without induction treatment. CONCLUSIONS: Induction treatment with interferon for 12 weeks and combination therapy for a total duration of 36 weeks could therefore be cost effective.