Open-label study of faldaprevir plus peginterferon and ribavirin in hepatitis C virus genotype 1-infected patients who failed placebo plus peginterferon and ribavirin.

Faldaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, was evaluated in HCV genotype 1-infected patients who failed peginterferon and ribavirin (PegIFN/RBV) treatment during one of three prior faldaprevir trials. Patients who received placebo plus PegIFN/RBV and had virological failure during a prior trial were enrolled and treated in two cohorts: prior relapsers (n = 43) and prior nonresponders (null responders, partial responders and patients with breakthrough; n = 75). Both cohorts received faldaprevir 240 mg once daily plus PegIFN/RBV for 24 weeks. Prior relapsers with early treatment success (ETS; HCV RNA <25 IU/mL detectable or undetectable at week 4 and <25 IU/mL undetectable at week 8) stopped treatment at week 24. Others received PegIFN/RBV through week 48. The primary efficacy endpoint was sustained virological response (HCV RNA <25 IU/mL undetectable) 12 weeks post treatment (SVR12). More prior nonresponders than prior relapsers had baseline HCV RNA ≥ 800,000 IU/mL (80% vs 58%) and a non-CC IL28B genotype (91% vs 70%). Rates of SVR12 (95% CI) were 95.3% (89.1, 100.0) among prior relapsers and 54.7% (43.4, 65.9) among prior nonresponders; corresponding ETS rates were 97.7% and 65.3%. Adverse events led to faldaprevir discontinuations in 3% of patients. The most common Division of AIDS Grade ≥ 2 adverse events were anaemia (13%), nausea (10%) and hyperbilirubinaemia (9%). In conclusion, faldaprevir plus PegIFN/RBV achieved clinically meaningful SVR12 rates in patients who failed PegIFN/RBV in a prior trial, with response rates higher among prior relapsers than among prior nonresponders. The adverse event profile was consistent with the known safety profile of faldaprevir.

Apolipoprotein E-ε4 deficiency and cognitive function in hepatitis C virus-infected patients.

Hepatitis C virus (HCV) causes not only liver damage in certain patients but can also lead to neuropsychiatric symptoms. Previous studies have shown that the type 4 allele of the gene for apolipoprotein E (APOE) is strongly protective against HCV-induced damage in liver. In this study, we have investigated the possibility that APOE genotype is involved in the action of HCV in brain. One hundred HCV-infected patients with mild liver disease underwent a neurological examination and a comprehensive psychometric testing of attention and memory function. In addition, patients completed questionnaires for the assessment of fatigue, health-related quality of life and mood disturbances. Apolipoprotein E gene genotyping was carried out on saliva using buccal swabs. The APOE-ε4 allele frequency was significantly lower in patients with an impairment of working memory, compared to those with a normal working memory test result (P = 0.003). A lower APOE-ε4 allele frequency was also observed in patients with definitely altered attention ability (P = 0.008), but here, the P-value missed the level of significance after application of the Bonferroni correction. Our data suggest that the APOE-ε4 allele is protective against attention deficit and especially against poor working memory in HCV-infected subjects with mild liver disease. Considering the role of apolipoprotein E in the life cycle of the virus, the findings shed interesting new light upon possible pathomechanisms behind the development of neuropsychiatric symptoms in hepatitis C infection.

Extended duration therapy with pegylated interferon and ribavirin for patients with genotype 3 hepatitis C and advanced fibrosis: final results from the STEPS trial.

BACKGROUND & AIMS: Patients with genotype 3 hepatitis C virus (HCV) infection and cirrhosis have poor response rates after 24 weeks treatment with pegylated interferon and ribavirin. Treatment for 48 weeks is therefore recommended, although the benefits of this are untested. We examined extended therapy in patients with genotype 3 HCV and advanced fibrosis. METHODS: Multicentre, open labelled randomized trial comparing therapy with 24 weeks pegylated interferon and ribavirin to 48 weeks of the same therapy. RESULTS: 136 patients completed the study. 67 received 24 weeks therapy and the SVR rate (48%) did not differ from that seen in the 69 patients who received 48 weeks therapy (42%). The response rates in patients with biopsy proven cirrhosis (13 patients treated for 24 weeks, 18 patients treated for 48 weeks) or cirrhosis proven on imaging (28 patients treated for 24 weeks and 25 patients treated for 48 weeks) were 46% in those treated for 24 weeks and 40% in those treated for 48 weeks. The differences were not significantly different. Treatment failure was due to relapse in the majority of patients. CONCLUSIONS: Patients with genotype 3 HCV and advanced fibrosis do not benefit from extended therapy with pegylated interferon and ribavirin.

Cerebral microglial activation in patients with hepatitis C: in vivo evidence of neuroinflammation.

Patients with chronic hepatitis C infection may exhibit neuropsychological symptoms and cognitive impairment. Post-mortem studies of hepatitis C virus HCV quasispecies and replicative intermediates indicate that the brain might act as a separate compartment for viral replication and microglia may be the locus for infection and subsequent neuroinflammatory activity. We sought to use two independent in vivo imaging techniques to determine evidence of neuroinflammation in patients with histologically mild chronic hepatitis C. Using positron emission tomography (PET) with a ligand for microglial/brain macrophage activation, (11)C-(R)-PK11195 (PK11195) and cerebral proton magnetic resonance spectroscopy, we determined whether there was evidence of neuroinflammation in a pilot study of 11 patients with biopsy-proven mild chronic hepatitis C, compared to healthy volunteers. Patients were characterized by cognitive testing and the fatigue impact scale to assess for CNS impairment. PK11195 binding potential was significantly increased in the caudate nucleus of patients, compared to normal controls (P = 0.03). The caudate and thalamic binding potential were more significantly increased in six patients with genotype 1 infection (P = 0.007) and positively correlated with viraemia (r = 0.77, P = 0.005). Basal ganglia myo-inositol/creatine and choline/creatine ratios were also significantly elevated in patients with chronic hepatitis C compared to normal controls (P = 0.0004 and P = 0.01, respectively). Using PET, we demonstrated evidence of microglial activation, which positively correlated with HCV viraemia and altered cerebral metabolism in the brains of patients with mild hepatitis C. This provides further in vivo evidence for a neurotropic role for HCV.

In vivo imaging of cerebral "peripheral benzodiazepine binding sites" in patients with hepatic encephalopathy.

BACKGROUND AND AIMS: One proposed mechanism whereby hepatic encephalopathy (HE) leads to loss of brain function is dysregulated synthesis of neurosteroids. Mitochondrial synthesis of neurosteroids is regulated by "peripheral benzodiazepine binding sites" (PBBS). Expressed in the brain by activated glial cells, PBBS can be measured in vivo by the specific ligand [11C](R)-PK11195 and positron emission tomography (PET). Recently, it has been suggested that PBBS expressing glial cells may play a role in the general inflammatory responses seen in HE. Therefore, we measured PBBS in vivo in the brains of patients with minimal HE using [11C](R)-PK11195 PET. METHODS: Five patients with minimal HE and biopsy proven cirrhosis of differing aetiology were assessed with a neuropsychometric battery. Regional expression of PBBS in the brain was detected by [11C](R)-PK11195 PET. RESULTS: All patients showed brain regions with increased [11C](R)-PK11195 binding. Significant increases in glial [11C](R)-PK11195 binding were found bilaterally in the pallidum, right putamen, and right dorsolateral prefrontal region. The patient with the most severe cognitive impairment had the highest increases in regional [11C](R)-PK11195 binding. CONCLUSION: HE is associated with increased cerebral binding of [11C](R)-PK11195 in vivo, reflecting increased expression of PBBS by glial cells. This supports earlier experimental evidence in rodent models of liver failure, suggesting that an altered glial cell state, as evidenced by the increase in cerebral PBBS, might be causally related to impaired brain functioning in HE.

Treatment of histologically mild hepatitis C virus infection with interferon and ribavirin: a multicentre randomized controlled trial.

Current guidelines advocate no treatment for patients with histologically mild hepatitis C virus (HCV) infection. This was a UK multicentre randomized controlled trial comparing alpha-interferon (3 MU thrice weekly) + ribavirin (1000-1200 mg/day) for 48 weeks with no treatment in treatment naive, adult patients with histologically mild chronic HCV infection. The aim was to compare benefits, safety and efficacy of combination therapy with alpha-interferon 2b and ribavirin for 48 weeks with no treatment (current standard management) in this patient group. In the treatment group 32 of 98 (33%) patients achieved a sustained virological response (SVR). Patients infected with genotype 1 had a lower SVR than those infected with genotype non-1 (18% vs 49% P = 0.02). No patients who failed to achieve a 2-log drop in viral load at 12 weeks achieved SVR. Improvements in quality of life 24 weeks postcessation of therapy compared with baseline using the SF-36 questionnaire measures were observed in the treated group. For patients with mild HCV infection with viral genotype non-1, the results are sufficiently good to suggest that therapeutic decisions should no longer be biopsy-driven. For patients infected with genotype 1, a liver biopsy is still indicated as the low chance of SVR is outweighed by an unacceptable burden of side-effects. Patients who fail to respond by 12 weeks of therapy should have their treatment curtailed early.

Fatigue and primary biliary cirrhosis: association of globus pallidus magnetisation transfer ratio measurements with fatigue severity and blood manganese levels.

BACKGROUND AND AIM: Fatigue is the commonest symptom in primary biliary cirrhosis (PBC), affecting individuals at all stages of disease. The pathogenesis of fatigue in PBC is unknown although rat models suggest a central nervous system (CNS) cause. We examined the hypothesis that a CNS abnormality related to cholestasis, rather than cirrhosis per se, underlies this symptom. PATIENTS AND METHODS: Fourteen patients with precirrhotic PBC (stage I-II disease), four patients with stage III-IV PBC, and 11 healthy women were studied using cerebral magnetisation contrast imaging and proton magnetic resonance spectroscopy (MRS). RESULTS: The globus pallidus magnetisation transfer ratio (MTR), a quantifiable tissue characteristic that may be abnormal in the presence of normal magnetic resonance imaging, was significantly reduced in precirrhotic PBC patients compared with healthy controls. These measurements correlated with blood manganese levels and were more abnormal in the more fatigued subjects. There were no differences in MRS measurements between the three study groups, suggesting that the abnormal MTR was not related to hepatic encephalopathy. CONCLUSION: This study suggests that impairments in liver function in PBC may adversely affect the brain long before the development of cirrhosis and hepatic encephalopathy, possibly as a result of altered manganese homeostasis within the CNS.

Cerebral dysfunction in chronic hepatitis C infection.

A number of studies have reported an association between chronic hepatitis C (HCV) infection and significant impairments in health-related quality of life (QOL), which are independent of the severity of liver disease. There are numerous reports documenting the prevalence of symptoms such as fatigue and depression in chronic HCV infection, which may in part account for the reductions in quality of life. Although there are a large number of potential explanations for these symptoms, including depression and anxiety associated with the diagnosis of HCV infection or substance abuse, there has been recent interest in the possibility of a biological effect of HCV infection on cerebral function. There is emerging evidence of mild, but significant neurocognitive impairment in HCV infection, which cannot be attributed to substance abuse, coexistent depression or hepatic encephalopathy. In vivo magnetic resonance spectroscopy and neurophysiological studies have suggested that a biological mechanism may underlie these cognitive findings. The recent detection of HCV genetic sequences in post mortem brain tissue raises the intriguing possibility that HCV infection of the central nervous system may be related to the reported neuropsychological symptoms and cognitive impairment.

Changes in brain intracellular pH and membrane phospholipids on oxygen therapy in hypoxic patients with chronic obstructive pulmonary disease.

Chronic hypoxia due to chronic obstructive pulmonary disease (COPD) constitutes a stress to cerebral metabolic homeostasis. Previous studies using phosphorus-31 magnetic resonance spectroscopy (31P MRS) have suggested that the brains of such patients utilize anaerobic glycolysis, which in neonatal, animal, and in vitro studies is associated with a protective intracellular alkalosis. To identify such a compensatory intracellular alkalosis in hypoxic COPD patients, in vivo cerebral 31P MRS was performed in eight patients and eight controls. The mean intracellular pH (pHi) in patients with COPD was similar to that of age-matched controls, but decreased in the patients with COPD by a mean pHi of 0.02 (p = 0.04), following supplemental oxygen. There was no change in cerebral pHi in normal subjects following oxygen administration. The broadband component of the MR spectrum increased in all the patients with COPD (p = 0.01), suggesting altered phospholipid membrane fluidity in the brain associated with the change in pHi following oxygen administration. The change in the broadband resonance was strongly correlated with the change in pHi (r = -0.68, p = 0.014). This study suggests that patients with COPD exhibit a compensatory change in pHi and abnormalities in cerebral membrane phospholipid conformation in the face of chronic hypoxia.

New insights into hepatitis C.

Hepatitis C infection is characterised by three key features, which are the consequence of a complex interaction between genetic determinants of immune and other host factors and viral characteristics: 1. A high rate of viral persistence after acute infection resulting from a combination of weak T cell responsiveness and specific viral mechanisms of immune escape. 2. Marked interindividual variability in end-organ damage (fibrosis and cirrhosis), probably due to host genetic polymorphisms in genes governing the immune response and fibrosis pathways in addition to viral pathogenicity factors. 3. Significant resistance to antiviral therapies. Viral mechanisms of antiviral resistance parallel those of viral persistence, and include the intriguing possibility that hepatitis C may infect immunologically privileged sites such as the central nervous system.

Evidence for a cerebral effect of the hepatitis C virus.

Patients with hepatitis C virus (HCV) infection frequently complain of symptoms akin to the chronic fatigue syndrome and score worse on health-related quality of life indices than matched controls. We address the hypothesis that HCV itself affects cerebral function. Using proton magnetic-resonance spectroscopy we have shown elevations in basal ganglia and white matter choline/creatine ratios in patients with histologically-mild hepatitis C, compared with healthy volunteers and patients with hepatitis B. This elevation is unrelated to hepatic encephalopathy or a history of intravenous drug abuse, and suggests that a biological process underlies the extrahepatic symptoms in chronic HCV infection.

Intracellular pH measurements of the whole head and the basal ganglia in chronic liver disease: a phosphorus-31 MR spectroscopy study.

The purpose of this study was to determine the intracellular pH of the whole head and in voxels localized to the basal ganglia in patients with chronic liver disease using phosphorus-31 magnetic resonance spectroscopy (31P MRS). The study group compromised 82 patients with biopsy-proven cirrhosis (43 Child's grade A, 25 Child's grade B and 14 Child's grade C). Eleven subjects showed no evidence of neuropsychiatric impairment on clinical, psychometric and electrophysiological testing, 37 showed evidence of minimal hepatic encephalopathy and 34 had overt hepatic encephalopathy. Unlocalized 31P MRS of the whole head was performed in 48 patients and 10 healthy volunteers. Localized 31P MRS of the basal ganglia was performed in the 34 patients and in 20 healthy volunteers. The intracellular pH values were calculated from the chemical shift difference between the inorganic phosphate (P) and phosphocreatine (PCr) resonances. The percentage inorganic phosphate (%Pi), phosphocreatine (%PCr) and betaNTP signals, relative to the total 31P signal, and peak area ratios of inorganic phosphate and phosphocreatine, relative to betaNTP were also measured. There were no differences between patients and volunteers in intracellular pH in 31P MR spectra measured from the whole head or the basal ganglia. There was no correlation between the severity of encephalopathy (West Haven criteria) or liver dysfunction (Child score) and intracellular pH values. There was also no significant change in the inorganic phosphate, phosphocreatine or betaNTP resonances in spectra acquired from the whole head. However, in spectra localized to the basal ganglia, there was a significant increase in mean P/NTP (p=0.02) and PCr/NTP (p=0.009). The mean %Pi and mean %PCr were also increased (p=0.06; p=0.05, respectively), but there was no significant change in mean %betaNTP. When the patient population was classified according to the severity of encephalopathy, those with overt disease had a higher mean P/NTP and %Pi (p=0.03; p=0.01), compared to the reference population. Our results suggest that there are detectable bioenergetic abnormalities in patients with minimal hepatic encephalopathy or stable, overt chronic hepatic encephalopathy, but any associated intracellular pH change is probably a secondary, rather than a primary phenomenon.

Possible mechanisms of action and reasons for failure of antiviral therapy in chronic hepatitis C.

The known mechanisms of hepatitis C virus (HCV) clearance and their failure in persistent infection are discussed. Interferon-alpha is the main treatment in chronic HCV but has shown poor sustained virological response rates when used as a monotherapy. The effects of interferon-a may include inhibition of HCV virion production by an effect on viral RNA and protein synthesis, enhancement of immune lysis of HCV infected cells, inhibition of hepatic fibrosis by an effect on TGFbeta, and an effect on HCV induced carcinogenesis. Mathematical modelling studies have provided insights into the mechanisms of action of interferon-alpha in chronic HCV. The two-phase plasma HCV RNA disappearance curve may reflect the presence of an interferon-resistant second site of HCV replication either within or outside the liver. Clinical observations and cerebral magnetic resonance scans provide evidence of functional cerebral impairment in HCV infected patients, raising the issue of the central nervous system (CNS) as a site for HCV replication. Recent studies using ribavirin in combination with interferon suggest that this approach doubles the sustained response rates obtained without having a major effect on the initial rate of HCV clearance (see Zeuzem paper). The potential mechanisms of action of ribavirin, although not yet fully understood, include inhibition of synthesis of GTP by an effect on inosine monophosphate dehydrogenase thereby limiting viral RNA synthesis, and enhancement of TH1 responses, which may assist viral clearance. There is no significant effect on HCV RNA polymerase activity. It is possible that ribavirin may have activity at extrahepatic sites of HCV infection, thus explaining the marked reduction in relapse rates with combination therapy, without an appreciable effect on initial antiviral response.