Evaluation of advanced fibrosis measured by transient elastography after hepatitis C virus protease inhibitor-based triple therapy.

AIM: Few studies have investigated the course of liver stiffness after treatment with protease inhibitors. We evaluated the impact of this therapy on liver fibrosis measured by transient elastography. METHODS: This multicenter observational, cohort, prospective study included 90 patients with hepatitis C genotype 1 treated with telaprevir or boceprevir who had advanced fibrosis evidenced by liver stiffness (≥9.5 kPa). Liver stiffness was measured at baseline and 24 weeks after treatment ended, and was compared with virological responses at week 12. RESULTS: Liver stiffness decreased in 89% of patients who achieved sustained virological response. The median intrapatient liver stiffness value at the end of follow-up decreased by 5.1 kPa (35%) from baseline compared with 0.1 kPa (0.5%) in those who did not achieve a sustained virological response (P<0.001). The liver stiffness level fell below 9.5 kPa in 58% of patients with sustained virological response, and 71% of those with sustained virological response and cirrhosis evidenced by liver stiffness at baseline achieved regression below 12.5 kPa by the end of follow-up. Sustained virological response was the only variable associated with improved liver stiffness in multivariate analysis (odds ratio: 17.3; 95% confidence interval: 4.4-67.6; P<0.001). CONCLUSION: In patients with advanced fibrosis measured by transient elastography at the beginning of protease inhibitor-based therapy with sustained virological response, liver stiffness was significantly reduced 24 weeks after treatment. This suggests the possibility of liver cirrhosis evidenced by liver stiffness regression after sustained virological response in a significant proportion of patients.

Barriers to HCV treatment in the era of triple therapy: a prospective multi-centred study in clinical practice.

BACKGROUND & AIMS: (i) To describe the demographic, clinical, virological and histological characteristics of the patients undergoing evaluation for indication of triple therapy against hepatitis C virus genotype 1, and to identify the reasons why candidate patients are excluded; and (ii) to evaluate the characteristics of the healthcare environment related to treatment. METHODS: Observational, prospective and multi-centred study involving 16 hospitals of Spain. Data were collected on 1122 patients receiving attention in the outpatient clinics between June and December 2012. RESULTS: Of the 1122 patients evaluated, 769 were finally included in this study; 27% (211/769) had contraindications to the therapy. Of those without contraindications, 54% (301/558) did not receive the treatment, and so, only about a third of the patients (33%-257/769) underwent therapy. The reasons for not initiating therapy were as follows: patient refusal (30%), mild disease/awaiting new treatments (34%), restrictions by the health service (30%), other reasons (6%). In univariate analyses, the probability of receiving treatment was related to: age <60 years, male gender, high education level, advanced fibrosis, having had previous treatment, being assessed in a centre of excellence. In multivariate analyses, the factors independently related to the probability of receiving treatment were as follows: high education level of the patients (P = 0.004), advanced fibrosis (P < 0.001) and centres of excellence (P = 0.009). CONCLUSION: Despite the high efficacy of triple therapy, only a small proportion of patients receive the treatment. The causes related to non-treatment depend on patient factors, disease stage and characteristics of the health-service provision.

Usefulness of combined measurement of serum bile acids and ferritin as additional prognostic markers to predict failure to reach sustained response to antiviral treatment in chronic hepatitis C.

AIM: To investigate the relationship between serum levels of ferritin and bile acids (BA) and the response to antiviral treatment in chronic hepatitis C (HCV). METHODS: A retrospective study was carried out on 35 control volunteers and 50 patients receiving interferon alpha-2b alone or plus ribavirin for 48 weeks. These were classified as sustained responders (SR) for >6 months after therapy (n = 17), non-responders (NR) (n = 27) and relapsers (RL) (n = 6). Before treatment, serum ferritin levels were determined by immunoturbidometry, 3alpha-hydroxyl-BA levels (S-3alpha-OH-BA) were assayed enzymatically and total (desulfated, deglucuronidated and deamidated) BA concentrations (STBA) by gas chromatography-mass spectrometry. RESULTS: STBA were lower in controls than in patients (SR < NR + RL). The highest levels of cholic acid and chenodeoxycholic acid families were found in NR + RL. Levels of cholic acid family were similar in controls and SR, whereas those of chenodeoxycholic acid family were higher in SR than in controls. A significant correlation between STBA (but not S-3alpha-OH-BA) and ferritin was found. Apparent value to predict the absence of a sustained response was calculated by combining elevated ferritin (>300 microg/mL) and STBA or individual BA species at different cut-off values. The best degree of certainty (100% specificity) was obtained using STBA >15 microM. CONCLUSION: These results recommend that larger prospective trials should be performed in chronic HCV patients to evaluate the usefulness of combined measuring of STBA and ferritin as additional prognostic markers to predict the existence of a very low probability of a sustained response to the current standard treatment, i.e. pegylated interferon in combination with ribavirin.

TNP-470 inhibits oxidative stress, nitric oxide production and nuclear factor kappa B activation in a rat model of hepatocellular carcinoma.

The objective of this study is to determine if treatment with the angiogenesis inhibitor TNP-470 results in impairment of oxidative stress, inhibition of nuclear factor kappa B (NF-kappaB) activation and decrease of nitric oxide production in an experimental model of rat hepatocarcinogenesis. Tumour was induced by diethylnitrosamine and promoted by two-thirds hepatectomy plus acetaminofluorene administration. Experiments were carried out at 28 weeks after initiating the treatment. TNP-470 was administered at 30mg/kg, three times per week from 20 to 28 weeks. Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Liver concentrations of thiobarbituric acid reactive substances, reduced glutathione (GSH) and glutathione disulfide (GSSG) were significantly higher than those of controls and there was a significant increase in the GSSG/GSH ratio. Tumour growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of (NF-kappaB) and proteolysis of IkappaB. All these effects were absent in animals receiving TNP-470. Our results indicate that TNP-470 inhibits oxidative stress, nitric oxide production and NF-kappaB activation induced by experimental hepatocarcinogenesis. These changes would contribute to the beneficial effects of TNP-470 in cancer treatment.

Caspase inhibition does not protect against liver damage in hemorrhagic shock.

This study was aimed to determine whether administration of an inhibitor of caspase-3 protects hepatocellular function in rats with hemorrhagic shock and whether caspases are important pharmacological targets in attenuating liver injury induced by hemorrhagic shock and resuscitation. Male adult rats were subjected to hemorrhagic shock by bleeding to a mean arterial blood pressure of 35-40 mmHg for 1 h and were then resuscitation with 60% shed blood and lactated Ringers solution. A subgroup of animals was injected i.v. with 2 mg/kg caspase inhibitor, Z-DEVD-FMK, prior to blood withdrawal. Fas ligand expression was markedly elevated and caspase-3 activity increased by 3-fold in hemorrhagic untreated rats. The increase in caspase-3 activity was prevented by administration of Z-DEVD-FMK prior to shock and resuscitation. Poly (adenosine diphosphate ribose) polymerase proteolysis was reduced in rats treated with the caspase-3 inhibitor compared with hemorrhagic untreated animals. Plasma aspartate aminotransferase and alanine aminotransferase values showed a significant increase at 6 h of shock in untreated animals (+360% and +515% as compared with sham-operated animals, respectively). Administration of the caspase-3 inhibitor did not prevent the increase in plasma transaminases. The cytosolic concentration of thiobarbituric acid-reactive substances (TBARS) and the oxidized:reduced glutathione ratio increased in the animals with hemorrhagic shock (+94% and +170%, respectively). These parameters were not significantly modified by pretreatment with Z-DEVD-FMK. It appears that caspase inhibition does not attenuate hepatocellular depression and liver injury induced by hemorrhagic shock and resuscitation.