Current antiviral combination therapy for chronic hepatitis C patients who failed to interferon alfa-based treatment.

WHAT IS KNOWN AND OBJECTIVE: Interferon-alfa-based therapy is effective in the treatment of Hepatitis C. However, some patients fail to respond and others relapse, after initially responding. Our objective was to assess the efficacy, safety and predictive factors for sustained virological response (SVR) to peginterferon plus ribavirin in chronic hepatitis C patients who failed to interferon-alfa (IFNα)-based therapy. METHODS: Seventy-five consecutive patients who failed to IFNα-based therapy were retreated with peginterferon plus ribavirin. Of these patients, 85% were infected by genotype 1. The primary endpoint was SVR. RESULTS AND DISCUSSION: Of 75 non-responder (n = 54) or relapser patients (n = 21), 50 were previously treated with IFNα-monotherapy and 25 with IFNα plus ribavirin. Global SVR rate was 41.3%: for patients re-treated with IFNα the response was 48% whilst for those retreated with IFNα plus ribavirin, it was 28%. For previous non-responders the SVR rate was 37% and for relapsers it was 52.4%. WHAT IS NEW AND CONCLUSION: Retreatment with peginterferon plus ribavirin is an effective option for some chronic hepatitis C non-responder or relapser patients. Higher SVR rate was achieved in relapsers and in those patients who received IFNα monotherapy previously.

Treatment regimens for patients with chronic hepatitis C.

Infection by the hepatitis C virus (HCV) is a major public health problem, with more than 170 million people infected throughout the world. The infection prevalence, with small regional differences, is estimated in 1-3% of the global population. HCV is the most frequent cause of chronic liver disease and 20-30% of patients develop cirrhosis with a risk of hepatocellular carcinoma. Nowadays, pegylated interferon-a (PEG-IFN) in combination with ribavirin, a nucleoside analogue, is the current treatment for chronic hepatitis C (CHC), with less adverse effects and better compliance. Dosage and duration depend on some factors as weight, genotype, viral load and a rapid virological response presented by the patient. One of the most relevant aspects in the treatment of CHC is how to manage the group of non-responder or relapser patients to previous treatments. As such, a substantial proportion of patients had already been unsuccessfully treated with interferon-based therapies and these patients claim for an optimal therapeutic option. The future treatment of CHC walk along through the association of two or three drugs, including nucleoside/nucleotide analogues, higher PEG-IFN initial dosages (induction) or longer treatments duration, or combination of helicase and protease inhibitors.

Clinical and pathological characteristics and response to combination therapy of genotype 4 chronic hepatitis C patients: experience from a spanish center.

This observational study evaluated the characteristics of genotype 4 chronic hepatitis C (CHC) patients and their response to combination therapy in Spain. 383 patients with CHC, 44 with genotype 4-HCV infection, were investigated. Nineteen genotype 4-HCV infected patients received IFNalpha-2b (3 MU three times weekly) plus ribavirin (1-1.2 g/day) and ten received Peg-IFNalpha-2b (1.5 microg/kg/week) plus ribavirin (1-1.2 g/day) for 12 months. A sustained virological response (SVR) was evaluated. Genotype 4-HCV was detected in 11.5% of patients, and was significantly associated with a higher proportion of infection through intravenous drug use (46% vs 11%; p<0.001), a higher alcohol intake (35% vs. 7%; p<0.001), higher proportion of anti-HBc positivity (41% vs. 22%; p<0.05), lower ALT (87+/-50 vs. 139+/-142 IU/L; p<0.001) and AST (53+/-30 vs. 85+/-126 IU/L; p<0.001) levels, lower viremia (4.1 +/- 7.7 (x 10(5)) vs . 7.3 +/- 9.8 IU(x 10(5) )/mL) p<0.05) and less fibrosis (stage 3-4 in 21% vs. 32%; p<0.06). Sixteen (55%) out of the 29 patients treated with combination therapy achieved a sustained virological response (SVR) while 10 (36%) were non-responders and 3 (9% relapsed. In conclusion, the lower stage of fibrosis, lower viremia and higher SVR rate than genotype 1 suggest a less aggressive pattern of diseased caused by this genotype.

Hepatitis crónica C: tratamiento de los pacientes no respondedores y con recaídas / Chronic hepatitis C: treatment of nonresponders with recurrence

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Transient elastography: a valid alternative to biopsy in patients with chronic liver disease.

BACKGROUND: Transient elastography is a novel and non-invasive technique for the evaluation of fibrosis in chronic liver disease. Few studies that exist value the efficacy of transient elastography, mainly in hepatitis C virus-infected patients. AIM: To evaluate the effectiveness, objectivity, reproducibility and safety of this technique. METHODS: We included 103 consecutive patients who underwent a liver biopsy in the last 48 months with a wide spectrum of chronic liver diseases. Median stiffness value (expressed as kilopascals - kPa) was kept as representative of the liver elastic modulus. All biopsy specimens were analysed by the same pathologist according to the METAVIR scoring system. RESULTS: Median value of stiffness in patients with mild or moderate fibrosis (FI and FII), and severe fibrosis or cirrhosis (FIII and FIV) was of 7, 4 +/- 5 and 16, 4 +/- 10 kPa, respectively, with a significant difference between them (P < 0.05). The areas under the receiver operating characteristic curves showed the optimal liver stiffness cut-off values for each group. CONCLUSIONS: We found a positive correlation between the liver stiffness found by transient elastography and fibrosis stage on biopsy in all patients, independently of the liver disease aetiology. Transient elastography is an easy, quick to perform and safe non-invasive procedure, reliable for assessing liver fibrosis.

Sustained virological response to peginterferon plus ribavirin in chronic hepatitis C genotype 1 patients is associated with a persistent Th1 immune response.

BACKGROUND: An impairment of cellular immune response may contribute to the persistency of hepatitis C virus infection. AIM: To analyse the Th1/Th2 cytokine profile in peripheral blood CD4(+) and CD8(+) T cells from patients with chronic hepatitis C (CHC) during treatment with pegylated interferon-alpha2a plus ribavirin and to correlate the Th1/Th2 balance with virological response (SVR). METHODS: Prospective longitudinal study: 44 naïve genotype 1 CHC patients received PEG-IFNalpha2a plus ribavirin for 48 weeks: 26 (59.1%) achieved a SVR, 13 relapsed (29.5%) and 5 (11.4%) were non-responders. Sixteen healthy controls were analysed. The production of IL-4, IFNgamma and TNFalpha by CD4(+) and CD8(+) T cells was measured using flow cytometry, both in resting and phorbol-ester-stimulated cells. RESULTS: First three months of treatment: the synthesis of TNFalpha by phorbol-ester-stimulated-CD4(+) T cells was higher in patients with SVR (P < 0.01). At the end of treatment, SVR was associated with higher intracellular expression of IFNgamma by stimulated-CD4(+) and CD8(+) T cells (P < 0.05). At the end of follow-up, a higher intracellular expression of IFNgamma by CD4(+) T cells was associated with a SVR. CONCLUSIONS: A Th1-type immune response was associated with achievement of a SVR, as indicated by the persistent elevation of intracellular IFNgamma and TNFalpha.

A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver injury. Currently, there are no proven effective therapies available. Atorvastatin is a new 3-hydroxy-3-metylglutaryl coenzyme A reductase inhibitor that reduces lipid serum levels. AIM: To evaluate the effectiveness and safety of atorvastatin in dyslipemid, non-alcoholic fatty liver patients. PATIENTS AND METHODS: We prospectively enrolled 25 patients with NAFLD; 22 of them completed the study. Body mass index, serum lipids, liver function tests and liver density assessed by echography were measured at baseline and after 1, 3, 6, 9 and 12 months of treatment. Normalization of transaminases and/or improvement in liver density were treatment end points. Patients received atorvastatin (10-80 mg/daily) according to basal serum choleresterol levels; additionally, they were given standard weight-loss counselling and encouraged to follow a low fat diet. RESULTS: All 22 patients (14 men, mean age 47 +/- 10 years) had high cholesterol levels at baseline and 11 (44%) also presented high trygliceride levels. After 6 months of treatment, eight patients (36.3%) presented normal transaminase levels. The remaining patients continued treatment for 12 months when 20% of patients presented with normal transaminase levels, while the other patients showed a 10% reduction in basal levels. Mean cholesterol levels were 268.5 +/- 44.2 and 186.8 +/- 14.4 mg/dL before and after treatment, respectively (P < 0.05). The mean body mass index was 27.4 +/- 3.1 at baseline and 26.3 +/- 2.8 kg/cm2 at the end of treatment (P > 0.05). No side effects were reported. CONCLUSIONS: Serum aminotransferase and lipid levels were reduced significantly in all patients with atorvastatin treatment. Therapy with atorvastatin in NAFLD patients with hyperlipidemia was found to be both effective and safe.

Maintenance of T1 response as induced during PEG-IFNalpha plus ribavirin therapy controls viral replication in genotype-1 patients with chronic hepatitis C.

OBJECTIVES: To analyze the T1/T2 cytokine profile in CD8 T cells from peripheral blood mononuclear cells from patients with genotype-1 CHC during treatment with pegylated interferon (Peg-IFN) alpha2a plus ribavirin (RBV). To correlate Th1/Th2 balance with virological response. PATIENTS AND METHODS: In this prospective longitudinal study, a total of 28 naïve genotype-1 CHC patients received Peg-IFNalpha2a (180 microg/week) plus RBV (1-1.2 g/day) for 48 weeks. All patients (mean age 45 +/- 8 years) completed treatment and follow-up: 12 (43%) achieved a sustained virological response (SVR), 13 relapsed after end of treatment (47%), and only 3 (10%) were non-responders. Sixteen healthy controls were also analyzed (mean age 39 +/- 17 years). The production of IL-4, IFNgamma, and TNFalpha by CD8 T cells was measured by intracytoplasmic detection using flow cytometry in both resting and stimulated cells with a phorbol ester. STATISTICS: Student's t test for independent values, chi2 test, and ANOVA test were used; relapsers and non-responders were joined to achieve a higher statistical power. RESULTS: At third month during treatment, phorbol ester-stimulated-IL-4 levels tend to be lower in patients who presented with SVR versus those who did not (0.97 vs 2.58; p = 0.1). No statistically significant differences were found in IFNgamma and TNFalpha levels at month 3. At EOT, the stimulated-IFNgamma production was significantly higher in patients with SVR (20 vs. 8; p < 0.05). Conversely, IL-4 production was higher in NR patients although these data did not reach statistical significance (p < 0.1). No significant differences were found in TNFalpha (14 vs. 7; p < 0.2). CONCLUSIONS: Cytokine T1 induced-response maintenance during combination treatment, measured as IFNgamma production by CD8+ T lymphocytes, is associated with SVR and suggests the replication control and later clearance of patients infected by genotype-1 HCV.

Therapeutic advantages of pegylation of interferon alpha in chronic hepatitis C.

Modification of the pharmacokinetic profile of interferon-alfa (IFNalfa) through pegylation (addition of a polyethylenglicol molecul) has resulted in a marked improvement of drug efficacy for the treatment of infection due to hepatitis C virus. Two pegylated derivatives of IFNalfa are available: PEG-IFNalfa-2a, with a 40 kDa polyethylenglicol molecule of branched structure, and PEG- IFNalfa- 2b, with a 12kDa linear PEG. Both compounds have slower absorption, more reduced distribution and lower elimination rate than the respective non- pegylated IFNalfa, which assures that concentrations appropriate to inhibit viral replication are maintained during longer periods of time, thus a allowing administration once a week, In addition to archieving greater therapeutic efficacy, the adverse effects related to excessive Cmax are reduced, the risk of therapeutic failure is decreased by eliminating the intervals of inefficient plasma levels, and the uncomfortable thrice weekly injection regimens are avoided. The current recommendations include the use of a combination therapy with pegylated IFNalfa and ribavirin as the standard treatment. However, further research is required to archieve dosage optimization of pegylated IFN and rebavirin according to the patients characteristics and to evaluate the efficacy and safety of this combined theraphy for difficult- to- treat patients.

Interferon-alpha plus ribavirin for 12 months increases the sustained response rates in chronic hepatitis C relapsers.

BACKGROUND: The effectiveness and tolerability of combination therapy for 12 months have not been evaluated sufficiently in chronic hepatitis C relapsers to interferon. AIMS: To evaluate the sustained response to interferon plus ribavirin for 12 months in chronic hepatitis C relapsers. METHODS: We included 55 chronic hepatitis C relapsers in a 12-month treatment protocol with interferon (3 MU thrice weekly) plus ribavirin (1-1.2 g/day). The effectiveness was evaluated using serum aminotransferase and hepatitis C virus RNA levels, alanine aminotransferase normalization and viraemia clearance after 12 months, defining the end-of-treatment response, and 6 months after completion of therapy, defining the sustained response. Adverse effects were recorded. RESULTS: End-of-treatment response and sustained response were achieved in 47 (85%) and 37 (67%) patients, respectively; there were 10 (21%) relapsers after combination therapy. Predictive factors of sustained response included the genotype (non-1 95% vs. 1 48%; P < 0.001), lower viraemia (503 917 +/- 553 230 vs. 901 393 +/- 548 267 copies/mL; P < 0.005), higher alanine aminotransferase levels (137 +/- 75 vs. 103 +/- 41 IU/L; P < 0.05) and a lower gamma-glutamyl transpeptidase/alanine aminotransferase ratio (0.30 +/- 0.23 vs. 0.49 +/- 0.39; P < 0.05). Tolerance to therapy was good, with no withdrawals. CONCLUSIONS: Interferon plus ribavirin treatment for 12 months in chronic hepatitis C relapsers yields high sustained response rates and is well tolerated. The sustained response is related to a non-1 genotype, lower baseline viraemia, higher alanine aminotransferase level and a lower gamma-glutamyl transpeptidase/alanine aminotransferase ratio.

Response to retreatment with interferon-alpha plus ribavirin in chronic hepatitis C patients is independent of the NS5A gene nucleotide sequence.

OBJECTIVE: Interferon-alpha plus ribavirin is an effective treatment for chronic hepatitis C patients. We evaluated whether the response to this combined therapy correlated with the presence of mutations in a region of 372 nucleotides within the NS5A gene. METHODS: Sixty-two patients, 42 nonresponders and 20 relapsers to a previous course of interferon-alpha, received 3 million units thrice weekly of interferon-alpha-2b and 1-1.2 g daily of ribavirin for 12 months. Basal biochemical and virological (HCV RNA and genotype) parameters were determined. Clinical examinations were carried out at 1, 2, 3, 6, and 12 months. In addition, nucleotide sequencing of the NS5A gene was determined for viral samples obtained from 38 of these patients at the baseline of the combined therapy, as well as in 15 of them before initiating the previous course of interferon as monotherapy. RESULTS: On finishing the 12 months, 36 patients (58.1%) had normal aminotransferases and 25 (40.3%) cleared viremia. Nucleotide sequencing indicated the same level of genetic variability within the group of responder and nonresponder patients all along the 124 amino acid residues of the NS5A gene studied. Neither the type of amino acid substitution nor the number of them was significantly different in one group relative to the other. CONCLUSIONS: Therapy with interferon-alpha-2b plus ribavirin was well tolerated, achieving an end-of-treatment response in 25 (40.3%) patients. Response did not correlate with the presence of mutations in the NS5A gene analyzed, including the interferon sensitivity determining region (ISDR) and its flanking sequences.

Chronic hepatitis C in children: a clinical and immunohistochemical comparative study with adult patients.

Limited information is available regarding the characteristics of the hepatitis C virus (HCV) infection in children. We compared the epidemiological background along with the virological and histological features as well as the intrahepatic immunologic phenotype of both children and adults with chronic hepatitis C (CHC). Serum samples of 24 pediatric and 32 adult patients were drawn for alanine transaminase (ALT) levels, HCV-typing, and viral load. The histological diagnosis and a semiquantitative immunohistochemical assessment were performed in all patients. The majority of children (62%) had been transfused and the mean duration of viral infection in these cases was 11 +/- 4 years, being similar in adults (11 +/- 9 years, not significant). Although genotype distribution was similar, viral load was lower in children than in adults. The mildest histological forms of chronic hepatitis along with a weak intrahepatic immunological phenotype were significantly more frequent among children than adult patients. In conclusion, in children with CHC, perinatal blood transfusion was the most frequent source of viral infection and the liver disease was characterized by both low ALT level and viral load, as well as the mildest histological and immunohistochemical forms of chronic hepatitis.

Interferon alpha with ribavirin for the treatment of chronic hepatitis C in non-responders or relapsers to interferon monotherapy.

BACKGROUND: A more effective therapy for chronic hepatitis C virus-infected patients is needed. AIM: To evaluate the efficacy, tolerance and timing of response to interferon alpha plus ribavirin in 60 patients with no response or reactivation after interferon alpha alone. METHODS: Sixty patients, 42 non-responders and 18 relapsers, received 3 million units three times weekly of interferon alpha-2b plus 1-1.2 g ribavirin daily, for 6 months. Basal biochemical and virological (HCV RNA and genotype) parameters were determined. Clinical examination, recording adverse effects, and laboratory tests, including viraemia, were carried out at 1, 2, 3 and 6 months. RESULTS: A significant (P < 0.001) progressive decrease of HCV RNA and alanine transaminase (ALT) levels was observed during treatment. On finalizing the sixth month, 42 patients (70%) had normal ALT and 26 (43.3%) were HCV RNA negative. Of these 26 complete responders, in 20 the viraemia was undetectable by the third month, while a late clearance at the sixth month of treatment was observed in six patients. Response rates were higher in previous responders to interferon alone (P < 0.05). Mild adverse effects appeared in 46 patients (79.6%), but only three were withdrawn due to serious side-effects. Significantly (P < 0.001), haemoglobin and leucocytes decreased, and bilirubin, ferritin and uric acid increased in the first month of treatment, with no changes thereafter. CONCLUSIONS: Interferon alpha plus ribavirin progressively decreased HCV RNA and ALT levels, achieving a complete response in the six months of treatment in 26 (43.3%) patients. This combined therapy was well tolerated.

[Acute pancreatitis in Caroli's syndrome]. / Pancreatitis aguda en un síndrome de Caroli.

Caroli's syndrome is included in the fibropolycystic abnormalities of the bile ducts. The disease is usually manifested by episodes of cholangitis. We report a case which presented as acute pancreatitis in the adulthood. The diagnosis was obtained by ultrasonography, CT scan, ERCP and liver biopsy. A choledochojejunostomy was performed with poor outcome and the patient is in the waiting list for liver transplantation.