January 27, 2012

Curing HCV For Many Coming

Written by Jules Levin from NATAP

There has been a lot of attention paid to this published study this week in the New England Jnl of Medicine, and rightfully so. It reports results that were however presented last April in 2011 at EASL, the European annual liver conference. The results of this study caused a landshift in HCV treatment, this study was the very first to find you could cure HCV without peginterferon+ribavirin. Before this study we thought perhaps we could do this, cure HCV without peg/rbv, but there was no data to support this yet. So the study investigators and BMS who developed the 2 oral HCV drugs used in the study gave 2 oral HCV drugs, an experimental NS5A inhibitor & an experimental HCV protease inhibitor only, no other HCV drugs, to the most difficult to treat patients: null responders, genotype 1 patients, patients that did not respond to previous peginterferon+ribavirin treatment. The only previous options for such patients was to be retreated again with peg/rbv and these studies found 10% response rates, very poor. This new study, granted only in 11 patients, found 36% 4/10 patients were cured with only the 2 new oral HCV drugs. Very interestingly 11 different patients in this study received 4 drugs, these 2 new oral HCV drugs plus peg/rbv and all 11 were cured. THIS STUDY PROVIDED PROOF-OF-CONCEPT that we can cure HCV+ patients without peg/rbv. Since this study was presented last April it has led to many researchers & drug companies to conduct studies to duplicate the same results in larger numbers of patients so we can fully characterize that we can eliminate peginterferon and ribavirin from therapy & to find the exact regimens that will accomplish this. Also companies are conducting studies trying to eliminate first peginterferon but keeping ribavirin in regimens, with excellent results. Multiple studies find that combining ribavirin with new oral HCV therapies but without peginterferon is very effective. So we will see in the near future regimens with 1 or 2 or maybe 3 new HCV drugs in combination with ribavirin, with I expect very high cure rates. At AASLD, the annual liver meeting in Nov 2011 Pharmasset reported in relatively small numbers of treatment-naive genotype 2/3 patients they cured 100% of patients with only 2 HCV dugs, their nucleotide PSI-7977 plus ribavirin, and after that conference Gilead bought Pharmasset for $11 Billion so they could have that drug PSI-7977 and so Gilead is developing therapies & treatment regimens including PSI-7977, and Gilead had already been developing their own additional HCV drugs in other classes including protease, NS5A & NNRTIs. BMS at the same time early last year started a study that included some treatment-naive genotype 1 patients receiving only 2 new experimental HCV drugs PSI-7977 plus their own NS5A inhibitor, results are expected soon, good results are anticipated. PSI-7977 is expected to begin phase 3 studies within months conducted now by Gilead, with an expected timeline of at most 2 years to get to the pharmacy unless this is expedited approval process by the FDA if results are very good, which I think is a possibility, there is precedence for accelerated approval. At the same time Tibotec started their own study with only 2 HCV drugs which includes again PSI-7977 plus the Tibotec HCV protease inhibitor and we are waiting for results. Last April 2011 Pharmasset reported results from a small study giving genotype 1 patients only 2 new experimental HCV drugs PSI-7977 and PSI-938, which is the other nucleotide they were developing and 95% cure rates were achieved without peg/rbv in genotype 1 patients. Some of the new drugs work only in genotype 1 patients but some of the new drugs are what is called pan-genotypic meaning they are effective for all genotypes 1 through 6. Since, very recently, news came out that PSI-938 was found to have a toxicity so the drug was put on hold but PSI-7977 continues on without any toxicities, and no toxicities have been seen in any other nucleotides. PSI-7977 is a nucleotide which is considered an important new class of HCV drugs because it is potent, once-daily administration, appears clean/few side effects and does not develop drug resistance at all so far. SO, a small biotech Inhibitex has developed INX189, a nucleotide that is in earlier development but was reported at AASLD in Nov 2011 to look as potent in studies in patients as PSI-7977, so BMS bought this company & this drug for $2.5 billion. At the same time, early in 2011 Vertex bought 2 nucleotides from a small biotech company called Alios. They have feverishly started new studies in late 2011 to examine & establish as quickly as possible the safety & potency of these drugs, with early results expected in early 2012, and of course with positive/encouraging results Vertex will very quickly develop & study these 2 nucleotides in studies in patients with perhaps a 2 year timeline for extensive data. Also currently in phase 3 are 2 new HCV protease inhibitors. As you know 2 brand new HCV protease inhibitors were approved by the FDA in the Summer of 2011, boceprevir (Victrellis) from Merck & telaprevir (Incivek) from Vertex. One of these 2 protease inhibitors plus peg/rbv increases cure rates to about 79% from the old standard of care of 40-45% in genotype 1 patients. Studies with telaprevir showed 79% SVR/cure rates, studies with boceprevir showed 69%% SVR/cure rates. These protease inhibitors are taken 3 times daily. Side effects associated with telaprevir include the possibility of skin rash & anemia & potential side effects associated with boceprevir is anemia. Currently in phase 3 are 2 new HCV protease inhibitors, the Boerhinger Ingelheim protease & the Tibotec HCV protease. Both are taken once daily. Also in phase 3 right now is a cyclophillin inhibitor, a new class of HCV drugs, called allisporivir, from Novartis. This drug appears to be potent as well. These 3 new drugs currently in phase 3 are expected in about 2 years to be in the pharmacy. Also, BMS is developing a potent, first-in-class NS5A inhibitor, as mentioned above. This drug is about to enter phase 3 if it hasn't already, and also is expected to become available in 2 years. In sum we have 2 new protease inhibitors now in the pharmacy & in 2 years expect 2 additional new protease inhibitors, and the nucleotide PSI7977 & the cyclophillin inhibitor allisporivir. PSI-7977 is likely to be able to be combined with a protease inhibitor but you cannot combine 2 protease inhibitors in the same regimen. The possibility of combining the cyclophillin inhibitor plus a protease inhibitor will be studied, I think we will be able to combine allisporivir with the nucleotide PSI7977 but of course that will have to be studied & confirmed. At the same time Abbott and Roche/Genentech are developing several of their new HCV drugs. Abbott has a potent HCV protease, 2 NNRTIs, and a NS5A inhibitor in studies in patients. Roche/Geentech has a potent HCV protease, a nucleoside, and a NNRTI in studies in patients. Both Abbott & Roche/Genentech are expected to report new study results soon at the EASL liver meeting in Barcelona this April, where we can also expect lots of new exciting study results from all these new drugs including peginterferon-sparing treatment and treatment regimens that include ribavirin but without peginterferon. There are several small biotech companies also developing drugs including Idenix, Achillion & Presidio, all of whom have interesting & promising HCV drugs. Achillion has 1st & 2nd generation NS5A inhibitors & protease inhibitors. Presidio has several promising NS5A inhibitors. Idenix has IDX1984 a nucleotide that appears to be less potent than these other nucleotides, and also has a protease & a NS5A. There are anywhere from 4 million to I estimate perhaps 8 million in the USA with HCV and an estimated 170 million globally with HCV-infection, but only 1 million have been tested & diagnosed in the USA and much less having been treated. So there is a gigantic undiagnosed patient pool in the USA & globally. It will however take tremendous resources/funds to provide adequate testing opportunities in the USA & of course globally. So far the US Federal government has provided next to nothing to conduct HCV testing in the USA. A small testing project funded by the NIH is expected to be announced in 2012 but it is likely to be too small to have adequate impact in diagnosing all the HCV+ patients in the USA, not to mention globally. We will I expect be able to cure close to 100% of treatable patients when the many the new drugs begin to become available in several years when we can put together various regimens comprised of 2, 3 or 4 oral drugs with or without peg/rbv. Another consideration is the aging-out of the HCV+ patient population. A large proportion of people with HCV were infected in the 1950s & 1960 and so are now in their 50s & 60s of age. It can take as long as 20-30 years for serious disease progression in many patients. So now serious liver disease is beginning to be reported in many aging patients, which means that unless diagnosed & treated these older patients with advanced liver disease are at great risk for serious disease complications & death. We need awareness campaigns & testing programs to identify & provide care for these patients. In addition there is a severe shortage of well trained clinicians who could take care of all these undiagnosed patients. we don't right now have enough clinicians to provide the care for so many patients. We need to be able to train new clinicians. Unlike in HIV where we have the $1 billion Ryan White Care Act which provides care & services for HIV+ individuals, there is no such program for HCV. This Care Act also supports funding for clinics where patients can receive care, and is particularly crucial for poor patients & marginalized patient populations. This program also provides free HIV drugs to uninsured patients. HCV Care & treatment is a difficult process for patients, who need care, treatment & support services including case management & crucial support services. Many HCV+ individuals are from severely marginalized patient populations including former & current IDUs, individuals receiving methadone maintenance. Some of these individuals need additional support services & special care. Conducting studies & providing special care clinics would be very important in providing adequate care for many of these patients. But again there so far is very little of this & funding from the Federal, State & City governments to provide such programs is basically totally absent. In sum, we will be able to cure close to 100% of HCV-infected treatable patients but we need funding & programs to better prepare to address the needs of many marginalized patient populations. Jules Levin

First Hepatitis C Treatment Data Demonstrating Proof of Principle with Direct-Acting Antiviral-only Therapy Published - BMS press release - (01/19/12)

Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1: 'this was the proof-of-concept study showing SVR ('cured') could be achieved without peg/rbv & with only 2 new oral HCV drugs' - (01/19/12)

The end of the beginning for hepatitis C treatment - (01/13/12) Commentary

The protease inhibitor GS-9256 and non-nucleoside polymerase inhibitor tegobuvir alone, with RBV or peginterferon plus RBV in hepatitis C - (01/13/12)

Dual therapy with the NS5A inhibitor BMS-790052 and the NS3 protease inhibitor BMS-650032 in HCV genotype 1b-infected null responders - (01/13/12)

Cost-effectiveness of hepatitis C virus antiviral treatment for injection drug user populations - (01/12/12)

HCV SVR Improves Quality of Life & Brain Function

Provided by NATAP

Download the PDF here

Download the PDF here

"The issue of whether the hepatitis C virus (HCV) affects brain function continues to arouse interest, investigation, and debate. Symptoms such as fatigue, poor memory, and concentration ("brain fog") are commonplace and an effect of this infection on mental health related quality of life, which is independent of liver fibrosis, is well established this study provides a substantial link between HCV and cerebral dysfunction by demonstrating a reduction in spectroscopic markers of cerebral inflammation and an improvement in cognition, following HCV eradication. While further larger-scale studies are required to confirm these findings, the cerebral benefit of HCV clearance should be recognized and considered an integral part of any anti-viral therapy dialog. SVRs demonstrated significant improvements in verbal learning, memory, and visuo-spatial memory..... This appears to be the first demonstration of improved cerebral inflammation and healthier neurocognitive function in SVRs and is directly attributable to the successful eradication of the virus......This study is important because it is the first to demonstrate that successful clearance of HCV infection can result in changes in cerebral metabolism that may underlie improvements in neurocognitive performance. The obvious weakness in this paper, which limits the conclusions that can be drawn at this time, is the small sample size"

SVR Improved Quality of Life & Sexual Function in Patients with Advanced Fibrosis in HALT-C Study - (02/20/07)

common co-morbidities found in patients with chronic hepatitis C, such as depression, diabetes, heart disease and obesity, are likely to contribute to the overall poor quality of life......disease stage is the major determinant of the effect of chronic hepatitis on HRQOL.....Patients with SVR had statistically significant improvements in physical and mental scores compared to baseline......these effects occurred even in patients with advanced fibrosis and cirrhosis In comparison to patients who responded and then relapsed, patients with SVR had statistically significant improvements in physical and sexual scores

Quality of life considerations for patients with chronic hepatitis C ...

www.natap.org/2009/HCV/081709_03.htm

Without treatment, however, patients with chronic HCV infection will be ... as well as brain imaging and evoked potential analyses have demonstrated that mild

Various novel agents, including telaprevir, boceprevir and longer-acting interferons such as albinterferon alfa-2b, appear to offer improved SVR rates and/or more convenient administration options compared with current therapies, potentially leading to improvements in HRQoL in patients with chronic hepatitis C.""

"Various studies have shown that HRQoL improves after SVR has been achieved [14,15,17-19]. A recent study of HRQoL in 29 patients receiving PEG-IFN-α showed that the 13 patients who achieved SVR after 12 weeks of treatment had significantly improved mental health summary scores on the SF-36 [14]. A recent analysis of data from the Hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial showed that SVR significantly improved scores in the role physical, general health, vitality, and role emotional domains of the SF-36. All patients in this trial had been previous nonresponders to antiviral therapy."
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Article in Press

Hepatitis C treatment - Clearing the mind

Jnl of Hepatology Jan 2012

Daniel M. Forton

Department of Gastroenterology and Hepatology, St. George's Hospital, University of London, London, UK

"SVRs demonstrated significant improvements in verbal learning, memory and visuospatial memory, which were not seen in the non-responders......What we found instead were improvements in the spectroscopic markers of cerebral inflammation (reductions in Cho and MI) in addition to improvements in selective cognitive domains, in patients who cleared virus following treatment with PIFN/R, an effect that was not observed in those who failed to respond to therapy. This appears to be the first demonstration of improved cerebral inflammation and healthier neurocognitive function in SVRs and is directly attributable to the successful eradication of the virus."

The issue of whether the hepatitis C virus (HCV) affects brain function continues to arouse interest, investigation, and debate. Symptoms such as fatigue, poor memory, and concentration ("brain fog") are commonplace and an effect of this infection on mental health related quality of life, which is independent of liver fibrosis, is well established [1]. However, despite convergent lines of evidence pointing to a biological effect of HCV within the CNS and some hypothesised mechanisms, there remains, as yet, a lack of incontrovertible evidence to definitively prove the fact. Parallels with HIV infection are commonly drawn, where AIDS related dementia is now rare with highly active anti-retroviral therapy (HAART) but milder neurocognitive impairments can persist despite immune reconstitution and viral suppression [2]. A degenerative brain process is not seen in HCV monoinfection and there remains doubt in the hepatology community as to whether HCV is a virus that can trigger neurological dysfunction. Furthermore, there does not appear to be a clinical consensus as to whether the relatively mild neurocognitive symptoms in HCV infection represent a significant or important element of the disease.

The possibility of a cerebral effect of HCV was raised ten years ago with the publication of proton magnetic resonance spectroscopy (MRS) and neuropsychological data, which showed evidence of altered cerebral metabolism and cognitive impairment in patients without advanced liver disease [3], [4], [5]. A number of further imaging studies, using MRS [6], [7], positron emission tomography (PET) and single-photon emission computed tomography (SPECT) [8] in patients without cirrhosis have demonstrated metabolic and neurochemical brain abnormalities, which differ to those described in hepatic encephalopathy. Rather, the findings suggest an inflammatory state within the brain with altered serotonergic and dopaminergic neurotransmission. In particular, elevated basal ganglia and white matter choline (Cho) and myo-inositol (mI), measured with proton MRS and often reported relative to creatine (Cr), are consistent with glial cell activation and proliferation and parallel changes observed in cerebral HIV infection [9], [10]. Reduced N-acetylaspartate (NAA) has also been reported in HIV and HCV monoinfections [6], [7].

A greater number of reports have documented mild but measureable cognitive deficits in patients with HCV infection, which are not readily accounted for by the severity of liver disease, associated recreational drug use or other potential confounding factors [11]. Although the studies have varied with respect to the degree to which confounders were excluded or controlled for and in terms of their cognitive assessment methodology, there is a reported pattern of deficits in attention, working memory, and learning ability with increased reaction times and relatively preserved accuracy. The prevalence of depression and anxiety was high in these reports but there do not appear to be clear associations between affective symptoms and cognitive function. However, fatigue, perhaps the commonest symptom in HCV infection, was reported to be associated with worse cognitive performance [6].

Despite the increasing body of descriptive literature, there are very few longitudinal reports of the effect of treatment and, in particular, of the effect of successful viral clearance on brain metabolism [12]. It is in this context that the small pilot study from Byrnes and colleagues, published in the current issue, is welcome [13]. Large treatment studies have demonstrated an improvement in HRQL and fatigue after a sustained virological response (SVR) to pegylated interferon and ribavirin but these studies have not generally blinded their subjects to treatment outcome and the knowledge of a "cure" is highly likely to skew results [14]. If the hypothesis to be tested were that a cerebral abnormality is due to HCV itself, objective demonstration of an improvement of that abnormality after SVR would be highly supportive of the hypothesis. Byrnes and colleagues report their findings in a small patient cohort which was studied with proton MRS and cognitive assessment before, during and after standard antiviral treatment with pegylated interferon and ribavirin. A second group of untreated patients was also studied at two time points. Overall, there were no significant changes in cerebral MRS during and after antiviral treatment. However, a sub-group analysis of viral responders and non-responders showed significant metabolic changes over time in the responder group only, consistent with normalisation of the metabolites, previously reported as elevated in HCV infection [9], [10]. Significant reductions were observed in basal ganglia Cho/Cr and mI/Cr ratios in SVRs (n=8) but not in non-responders or relapsers (n=6). The authors interpret this as an improvement in cerebral immune activation in those who cleared the virus. Patients in the treated and untreated groups tended to show an improvement in cognitive function over time, which was ascribed to a practice effect on the cognitive battery. However, when responders and non-responders were compared again, SVRs demonstrated significant improvements in verbal learning, memory and visuospatial memory, which were not seen in the non-responders.

This study is important because it is the first to demonstrate that successful clearance of HCV infection can result in changes in cerebral metabolism that may underlie improvements in neurocognitive performance. The obvious weakness in this paper, which limits the conclusions that can be drawn at this time, is the small sample size. The significant findings are only seen in a sub-group analysis, with very small groups. It is possible that a treatment effect was not seen in the non-responders because of a type II error. Furthermore, the absence of a healthy control group prevents conclusions about the importance of the observed changes. In a study published this year, Pattullo and colleagues also used MRS to assess the effect of SVR on brain metabolism [12]. In a larger study of 40 patients (31 SVRs and 9 non-responders) significant increases in globus pallidus Cho/Cr and NAA/Cr were seen in SVRs after treatment compared to baseline. These changes were not associated with cognitive measures, which did not improve with viral eradication. The opposite effect of viral eradication on Cho/Cr in the report from Byrne and colleagues is not readily explained but may be related to different patient characteristics, voxel position and acquisition parameters. Pattullo does however report reductions in globus pallidus NAA/Cr at baseline compared to controls, which increased significantly in the SVRs. Despite this, the authors concluded that when all other causes for cerebral dysfunction are excluded, viral clearance does not contribute to significant changes in brain function or biochemistry.

There are a number of strands of evidence, in addition to clinical data, that support a biological effect of HCV on the brain. Positive and negative strand HCV genetic sequences have been amplified from RNA extracted from human post-mortem brain samples and quasispecies analyses suggest replication within the CNS, albeit at a low level [15], [16]. Immunohistochemical staining for HCV non-structural protein 3 (NS3) in brain tissue suggests that astrocytes and microglia might be the host cell for HCV infection [17]. Gene expression analysis in laser dissected microglia, which stained with antibodies against HCV NS3, revealed up-regulation of proinflammatory genes such as TNF alpha and IL-1b that was not seen in NS3-ve microglia or in cells from HCV-ve individuals [18]. There are emerging in vitro data to support neuroimmune activation by HCV [19] and a recent report demonstrated that a human neuroepithelioma cell line expressed HCV entry receptors and allowed productive infection by the JFH-1 HCV strain, being the first non-hepatocyte line to do so [20].

These studies lead to the hypothesis that certain HCV variants or strains may gain entry to the CNS in susceptible individuals, to replicate at low but sufficient levels to cause immune activation of resident microglia, triggering established pathways that result in neuronal dysfunction [21]. In this hypothesis, successful viral eradication might reverse or attenuate the process, as suggested by the preliminary data from Byrnes and colleagues. If this is the case, it will be of interest to discover whether the evolving interferon-free regimes of direct acting anti-virals have the same effect or whether neurocognitive impairments could persist as in the case of HAART for HIV infection. Alternatively, one might consider that eradication of HCV from the liver results in normalisation of a chronic low-level inflammatory state, with concomitant improvements in brain function and metabolism secondary to a reduction of abnormal signalling, possibly by cytokines, from the periphery across the blood brain barrier.

The pilot study from Byrnes and colleagues is small but it serves to re-energise the debate as to whether there is a virological effect of HCV on brain function. A better knowledge of this is important for our understanding of the natural history of this infection and the symptoms it causes and for our ability to design appropriate therapeutic regimes. Further large studies are now indicated to determine whether successful antiviral treatment is definitively associated with improvements in brain biochemistry and function.
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Article in Press

Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition

Jnl of Hepatology

Jan 2012

Valerie Byrnes1, Anne Miller2, Damien Lowry4, Erin Hill2, Cheryl Weinstein2, David Alsop3,Robert Lenkinski3, Nezam H. Afdhal1,

1Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States;

2Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; 3Department of Radiology, Beth

Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; 4Liver Centre, Mater Misericordiae University
Hospital, Dublin 7, Ireland

Background & Aims

Chronic hepatitis C virus (HCV) infection is associated with altered cerebral metabolism and cognitive dysfunction. We aimed to evaluate the effect of pegylated interferon/ribavirin (PIFN/R) and HCV clearance on cerebral metabolism, and neuropsychological performance.

Methods

Fifteen non-cirrhotic HCV positive subjects underwent 1H MR spectroscopy (MRS) before, during, and after treatment with PIFN/R. The metabolites of interest namely, N-acetylaspartate (NAA), choline (Cho), myo-inositol (MI), and the control metabolite creatine (Cr), were acquired from 3 different brain regions; left basal ganglia, left frontal cortex, and left dorso-lateral pre-frontal cortex. Coinciding with this, subjects also underwent a battery of neuropsychological tests to evaluate the domains of verbal learning, memory, attention, language, executive functioning, and motor skills. Seven HCV positive controls (not receiving anti-viral therapy) underwent MRS and neuropsychological testing at two time points, 12weeks apart, to examine for variation in cerebral metabolites over time and the practice effect of repeat neuropsychological testing.

Results

Significant reductions in basal ganglia Cho/Cr (p=0.03) and basal ganglia MI/Cr (p=0.03) were observed in sustained virological responders (SVRs, n=8), but not non-responders/relapsers (NR/R, n=6), indicative of reduced cerebral infection and/or immune activation in those who cleared virus. SVRs demonstrated significant improvements in verbal learning, memory, and visuo-spatial memory. A small but significant improvement in neurocognitive function secondary to the practice effect was seen in both HCV controls and HCV subjects during treatment.

Conclusions

HCV eradication has a beneficial effect on cerebral metabolism and selective aspects of neurocognitive function and is an important factor when contemplating anti-viral therapy in HCV, especially in those with mild disease.

Introduction

Until recently HCV related neurocognitive dysfunction was believed to be a consequence of cirrhosis associated hepatic encephalopathy [1]. Several studies subsequently demonstrated cognitive dysfunction in non-cirrhotic HCV patients, when compared to age- and education-matched controls [2], [3], [4], [5], [6], [7], [8]. Selective impairments in the neurocognitive domains of attention, concentration, and working memory appear to predominate across studies [1], [2], [8]. While it has been contended that poorer neuropsychological test performance may in fact be attributable to the many confounding factors associated with the heterogeneity of hepatitis C patient populations [1], [9], [10], there is a growing body of evidence supporting the hypothesis that the hepatitis C virus may adversely affect cognition through direct central nervous system (CNS) involvement [1], [10], [11], [12].

HCV sequences have been demonstrated in CSF and brain tissue (at autopsy) in chronically infected individuals, suggesting that HCV may cross the blood-brain-barrier [12], [13], [14]. There is also evidence that HCV replicates within certain cell populations in the brain, namely macrophages and microglial cells [15]. Studies using proton MR spectroscopy have demonstrated altered cerebral metabolism in HCV, even in patients with mild liver disease [8], [9], [10], [11]. Elevated choline (Cho) and myoinositol (MI) ratios have been found in the basal ganglia, central, and frontal white matter of HCV-infected patients [9], [10], [11]. These findings are reflective of glial cell inflammation or proliferation. In addition, decreased levels of n-acetyl aspartate (NAA) have been observed in the central white matter of HCV-infected patients, suggestive of reduced neuronal integrity or neuronal 'drop-out' [8], [9]. Of particular interest is a recent finding by Forton et al. of increased MI/Cr ratios in the frontal white matter of HCV-infected patients that negatively correlated with working memory performance [11]. This was the first demonstration of a significant relationship between the observed metabolite abnormality, and a neurocognitive correlate, suggesting that a metabolite disturbance might in fact underlie a functional property of the brain. Another study demonstrated improved neurocognitive function following successful anti-viral treatment for HCV [16]. However, longitudinal studies on the effect of anti-viral therapy and viral clearance in HCV subjects are lacking.

This investigation sought to examine the cerebral effects of anti-viral therapy and HCV clearance in patients with mild HCV-related liver disease. We hypothesized that eradication of HCV would be associated with improved neurocognitive function as determined by MRS and neurocognitive testing, but that this may be offset by the adverse effects of PIFN/R. Demonstration of improvements in cerebral metabolism and cognition following viral eradication would strengthen the biologic link between HCV and cerebral dysfunction and may influence the criteria for patient selection for antiviral therapy in the future.

Results

Clinical characteristics during longitudinal follow-up
Twenty-two patients were enrolled in the study, 15 treatment candidates and 7 HCV controls. Patient characteristics are presented in Table 1. Mode of HCV acquisition in the treatment group was as follows; blood transfusion (n=5), injection drug use (n=5), occupational (n=1), tattoos (n=1), cocaine snorting (n=1), and unknown (n=2). Genotype 1 was the predominant genotype in 12/15 patients while the remaining 3/15 had genotype 3.

One patient could not complete the MRI component of the study due to undiagnosed claustrophobia and another could not complete the neuropsychological assessment accurately due to non-proficiency in the English language. Another stopped PIFN due to intolerable side effects, dropped out of the study after 12weeks, and was lost to follow up. Thus, complete MRS data was available on 14/15 subjects at time 1 and 2, but 13/15 subjects for all 3 time points. Similarly, complete neuropsychological assessment was available for 13/15 at all 3 time points. All controls completed both MRI/MRS and neuropsychological testing at the 2 time points.

Of the 15 treated patients, 13 had undetectable HCV RNA by quantitative testing (<600IU/ml) at week 12 of treatment (Time 2). One patient had a reduction in HCV RNA from 395,000 to 5500IU/ml, and the remaining patient had no change in HCV RNA level and discontinued PIFN after a total of 24-week treatment. By Time 3, 8/13 patients were persistently HCV RNA negative and proved to be SVRs. The remaining 5 tested HCV RNA positive.

MRS

Table 2 provides a breakdown of cerebral metabolite ratios (NAA/Cr, Cho/Cr, MI/Cr) in the basal ganglia, frontal cortex, and dorso-lateral pre-frontal cortex (DLPFC), for all study subjects. There was no significant difference in baseline measurements of cerebral metabolites between HCV treated patients and controls. In addition, cerebral metabolite levels remained constant in the control group, indicating a lack of significant change over time.

A significant reduction was observed in Cho/Cr in the basal ganglia of SVRs at Time 3 when compared to baseline (-32%, p=0.03), this effect was not seen in NR/R (-11%, p=0.8) (Fig. 2). Likewise, a significant reduction in MI/Cr was observed in the basal ganglia of SVRs at Time 3 when compared to baseline (-11%, p=0.03), whereas basal ganglia MI/Cr slightly increased in NR/R (+2%, p=0.7) (Fig. 3). Non-significant reductions were also noted in Cho/Cr ratio measured from the DLPFC in SVRs (-24%, p=0.3) and NR/R (-5%, p=0.6) at Time 3 when compared to baseline Table 3. Interestingly, the significant decrease in basal ganglia Cho/Cr from baseline was observed as early as Time 2 (i.e., 12weeks on treatment) in subjects who subsequently achieved and SVR, although the decline did not reach significance, there was a trend towards significance (-32%, p=0.06). No differences in NAA/Cr were observed between any of the time points examined.

Neuropsychological

Minor differences were observed between HCV controls and HCV treatment candidates at baseline on select measures of working memory (Letter number sequencing; U=14.0, z=-2.21, p=0.03) in addition to immediate visuo-spatial planning and memory (ROCF copy, U=15.0, z=-2.57, p=0.01; sROCF copy, U=8.5, z=-3.0, p=0.002 respectively), indicating poorer performance in the HCV control group Table 4. It must be noted that while differences appear between groups, case summary analysis reveals no HCV candidate scored within a clinically impaired range on letter number sequencing whereas 2 (both HCV controls) exhibited impaired scores on the ROCF copy.

At the time of last follow up (Time 3), SVRs had significant improvements in total verbal learning recall (z=-2.02, p=0.04), verbal memory recognition (z=-2.21, p=0.03) and visuo-spatial memory (z=-1.99, p=0.04) when compared to baseline. This trend was not matched in non-responders/relapsers. Moreover, while improvements across verbal recognition and visuo-spatial memory domains were within a 'healthy' normative range, the median scores for total verbal learning recall were 2 SDs below the normative mean in the case of HCV controls and 1.4 SDs below in the case of HCV treatment recipients. Case summary analyses revealed between 50% and 71% of all HCV study participants exhibited impaired scores on verbal learning domains at baseline. Additionally, retrospective analysis showed that little difference in cognition existed between SVRs and NR/R at baseline with NR/Rs performing worse relative to SVR counterparts only on a measure of visuo-spatial memory (U=6.5, z=-2.143, p=0.035, r=0.59).

Furthermore, significant improvements among HCV controls were observed across 6 neurocognitive test subsections from baseline to Time 2. These include improvements in total verbal learning (z=-2.19, p=0.03), delayed verbal recall (z=-2.04, p=0.04), visuomotor construction (z=-2.19, p=0.03), visuo-spatial immediate and delayed memory (z=-2.37, p=0.02; z=-2.12, p=0.03) in addition to cognitive flexibility (z=-2.06, p=0.04) likely due to the practice effect of repeat neuropsychological testing. When all HCV participants undergoing PIFN treatment were grouped together, they were also seen to improve in four areas from baseline to Time 2, namely verbal recognition (z=-2.59, p=0.01), visuo-spatial immediate and delayed memory (z=-2.85, p=0.004) as well as working memory (z=-2.00, p=0.04) further suggesting the effect of practice from Time 1 to Time 2.

Subjective health questionnaires

Depression scores increased in subjects following 12weeks of PIFN therapy when compared to baseline (z=-2.28, p=0.02). Median scores increased from 6 at baseline to 14.5 on treatment reflecting clinically significant levels. Analyses also revealed significant reductions on treatment in composite score estimates of physical and mental functioning (z=-1.96, p=0.05; z=-2.52, p=0.01). Restored 'healthy' levels of reported depressive symptomatology, physical, and mental health functioning were observed following the cessation of treatment, (Time 3).

Discussion

This study sought to investigate the cerebral effects of anti viral therapy in patients with mild chronic HCV. Our findings failed to demonstrate adverse effects of PIFN on cerebral metabolism or cognition. What we found instead were improvements in the spectroscopic markers of cerebral inflammation (reductions in Cho and MI) in addition to improvements in selective cognitive domains, in patients who cleared virus following treatment with PIFN/R, an effect that was not observed in those who failed to respond to therapy. This appears to be the first demonstration of improved cerebral inflammation and healthier neurocognitive function in SVRs and is directly attributable to the successful eradication of the virus.

Cho and MI are putative markers for glial cell inflammation and activation. Elevated levels of Cho in HCV positive subjects is believed to reflect cellular proliferation due to infection or inflammation [2], [9]. MI is found only in glial cells and is also a constituent of membrane lipids [18]. Increased levels are believed to reflect glial cell activation and increased cell membrane turnover [11], [19], [20]. While the exact pathogenesis of glial activation in HCV is unclear, HCV RNA has been found in brain tissue and within the CSF of HCV infected individuals supporting direct infection of the central nervous system [21], [22], [23], [24], [25]. One hypothesis is that HCV may be introduced to the CNS via infected monocytes ('Trojan Horse' mechanism) and can infect brain microglial cells, which are essentially tissue resident macrophages of blood monocytic origin [26]. Alternatively, glial activation and inflammation in HCV may occur indirectly due to the mediation of peripherally derived pro-inflammatory cytokines such as 1L-6, IL8, IL12, and TNF-α [27], [28], [29], [30]. Our finding of statistically significant reductions in Cho/Cr and MI/Cr in the basal ganglia following HCV eradication is suggestive of reduced glial cell inflammation ('gliosis') and adds support to the biologic link between HCV and cerebral metabolism as suggested by numerous other studies [1], [8], [10], [30]. Trends towards significance exist in relation to the decline in basal ganglia Cho/Cr following 12weeks of PIFN/R in both SVRs and the HCV patient group as a whole. The latter observation is likely due to the high proportion of patients who were serum HCV RNA negative at this time point. Interestingly, significant reductions in basal ganglia MI and non-significant reductions in basal ganglia Cho have also been reported in HIV positive subjects following initiation of aggressive anti-retroviral therapy [20]. We did not observe increased cerebral NAA following HCV eradication. Two studies have shown reduced NAA in HCV positive subjects when compared to HCV-negative controls, suggestive of reduced neuronal viability [8], [9]. No observed 'restoration' of NAA in the current study may be due to voxel positioning, which did not include the occipital grey matter, a site of reduced NAA in prior studies. Moreover, in spite of the etiology of neuronal loss, neuronal regeneration, as indicated by increased levels of NAA, is an unlikely expected occurrence over the time frame of this study if it at all [20].

Coinciding with a reduction in the markers of cerebral inflammation, we found statistically significant improvements in neurocognitive performance among SVRs at the time of last follow up when compared to baseline, a trend not observed among NR/R. Areas of improvement fall particularly within verbal memory domains but also visuo-spatial abilities. It is likely that these improvements are attributable to the successful eradication of virus as NR/R exposed to the same testing procedures did not exhibit such improvements, although it is conceded that larger group sizes would strengthen such conclusions.

It must be noted that significant improvements in test performances were observed across a number of cognitive domains among both HCV controls and treatment recipients at Time 2 compared to baseline. While HCV treatment recipients reported significant deterioration in mood and HRQoL functioning, it was not associated with any deleterious effect on cognition, contrary to our working hypothesis at the outset. In fact, the opposite proved true with a number of significantly improved performances following 12weeks of PIFN/R treatment. It would appear improvements at this juncture were likely to result from a practice effect as demonstrated by concomitant improvements in the HCV control group. These findings signal caution around interpreting data from repeat neuropsychological testing of patients using short interim periods. Validity of neurocognitive test outcomes can be optimized when test sittings occur after a minimum of 6months.

This study is not without its limitations. Firstly, its small sample size may have precluded the finding of a treatment effect in the NR arm. Secondly, we also employed the use of multiple comparisons, increasing the likelihood of type I errors. We felt that the use of a Bonferroni correction for such a pilot study would have been too conservative increasing the risk of incorrectly failing to find a treatment effect. In spite of these limitations and the preliminary nature of this study, the improvements in the variables examined were consistent across the SVR group and absent from the NR/R group, but larger studies are required to validate this.

In conclusion, this study provides a substantial link between HCV and cerebral dysfunction by demonstrating a reduction in spectroscopic markers of cerebral inflammation and an improvement in cognition, following HCV eradication. While further larger-scale studies are required to confirm these findings, the cerebral benefit of HCV clearance should be recognized and considered an integral part of any anti-viral therapy dialog.

Source

GEN News Highlights: Jan 9, 2012

Scientists have identified what they claim is a new target for preventing HCV infection, and also demonstrated that an existing FDA-approved cholesterol-lowering drug may fit the bill as a therapeutic agent against the disease. Building on previous research implicating viral cholesterol as a key factor in facilitating the entry of HCV into host cells, a team led by researchers at the University of Illinois-Chicago identified the cellular Neimann-Pick C1-like 1 (NPC1L1) cholesterol uptake receptor as a key HCV entry factor that is amenable to therapeutic intervention. Their work in addition showed that the FDA-approved NPC1L1 antagonist ezetimibe not only inhibits infection by all major HCV genotypes in vitro, but also delays the establishment of HCV genotype 1b infection in mice with human liver grafts.

Susan L. Uprichard, M.D., and colleagues report their findings in Nature Medicine in a paper titled “Identification of the Niemann-Pick C1–like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor.”

HCV is believed to enter cells via receptor mediated endocytosis, a process that likely involves the interaction of multiple viral particle molecules with a series of cell surface receptors. For example, the researchers note, infectious HCV virus in cell culture (HCVcc) is enriched in cholesterol, which prior research has demonstrated is required for HCV cell entry and infectivity.

This phenomen led the team to postulate whether cholesterol-uptake receptors other than SR-BI and LDLR might play a role in HCV cell entry. They focused on the cellular NPC1L1 cholesterol uptake receptor, a 13-transmembrane-domain cell surface cholesterol-sensing receptor that is expressed on the apical surface of intes­tinal enterocytes and human hepatocytes, including Huh7 cells.

Initial analyses indicated that, as with other HCV entry factors, NPC1L1 was downregulated in HCVcc-infected Huh7 cultures, and there was a marked reduction in NPC1L1 protein levels as early as four days after infection. Moreover, when NPC1L1 expression in Huh7 cells was silenced using a targeted siRNA, the cells were much less susceptible to HCVcc infection. Reduced susceptibility to HCVcc infection was also observed in Huh7 cells transfected wtih siRNA targeting either of the known HCV entry factors CD81 or SR-BI. This reduction in susceptibility to infection by HCVcc associated with siRNA transfection of Huh7 cells was found to be HCV- and HPC1L1-specific. Interestingly, though, NPC1L1 silencing had no effect on HCV subgenomic RNA replication, full-length infectious HCVcc RNA replication, or secretion of de novo HCVcc.

The results thus far indicated that HCV infection was inhibited at a step before RNA replication or secre­tion, so the team next evaluated the impact of antibody-mediated blocking of cell surface NPC1L1. Compared with cells treated using control IgG antibodies, those treated using antibodies specific to either NPC1L1 or the known HCV cell entry factor CD81 demonstrated notably reduced infection by HCVcc, as measured by intracellular HCV RNA levels. Using antibodies specific to each of the three large extracellular loops (LELs) of NPC1L1, the researchers were also able to determine that HCV infection was reduced only when NPC1L1 LEL1, but not LEL2 or LEL3, was blocked.

They then evaluated treatment using the FDA-approved cholesterol-lowering drug ezetimibe (which acts as a direct inhibitor of NPC1L1) either before, during, or after viral inoculation. The effects were measured using HCVcc foci-reduction assays, to quantify foci after ezetimibe treatment. The results showed that the drug reduced HCVcc foci formation in a dose-dependent manner when it was administered either before infection and then removed, or during virus inoculation, but not when treatment was carried out after inoculation.

Dose-responsive, time-of-addition–dependent inhibition of HCV infection was also evi­dent when HCV RNA levels were measured, and ezetimibe sensitivity was seen across a panel of HCVcc clones representative of HCV genotypes 1-7. “Hence, the data support the conclusion that direct pharmacological inhibition of NPC1L1 reduces HCV infection by directly inhibiting viral cell entry,” the authors write.

Further studies indicated that while although HCV can efficiently still bind to ezetimibe-treated cells, the drug blocks a post-binding step, and indeed prevents HCVcc cell entry either at or before virion-host cell fusion.

To confirm whether the dependence of HCV cell entry on NPC1L1 is actually related to the cholesterol in the HCV virions, the researchers devised a study to evaluate the dependence on NPC1L1 of viruses containing different amounts of cholesterol. This demonstrated that the cholesterol-rich strain of HCVcc was strongly dependent on NPC1L1 for cell entry, and was hypersensitive to ezetimibe-mediated inhibition. In contrast, when NPC1L1 was silenced or inhib­ited by ezetimibe, the cholesterol-scarce strain showed NPC1L1-independent cell entry and insensitivity to ezetimibe inhibition. “Together, these data reveal a correlation between the amount of virion-associated cholesterol and dependence on NPC1L1 for HCV cell entry,” they write.

In a final set of experiments the authors evaluated the involvement of NPC1L1 in HCV cell entry in a mouse model of acute HCV infection. Animals were treated with ezetimibe either two weeks, one week, or two days before challenge with HCV genotype 1b-positive serum. In the mice pretreated using the drug for two weeks before infection, HCV infection was significantly delayed, whereas ezetimibe was less effective at delaying infection in animals pretreated for just one week. In contrast, ezetimibe treatment was completely ineffective at delaying infection in mice receiving the drug just two days before challenge with HCV-infected serum.

More specifically, while all control mice were serum-positive for HCV by one week after challenge, 71% and 43% of mice treated with ezetimibe for two weeks and one week before infection were HCV negative, respectively. And of the five mice in the two-week ezetimibe pretreatment group that were HCV negative at week one, two were completely protected, remaining HCV negative at weeks two and three after infection, the authors note.

“Our finding that ezetimibe can delay the establishment of HCV genotype 1 infection in mice confirms the involvement of NPC1L1 in HCV infection in vivo and highlights the therapeutic potential of further pursuing the refinement or develop­ment of anti-NPC1L1 therapies for the treatment of HCV,” they conclude. What does remain to be determined, the team admits, is whether NPC1L1 directly interacts with HCV or indirectly participates in HCV entry by removing virion-associated cholesterol, possible to reveal protected viral glycoprotein binding sites or confer a required conformational change. Nevertheless, they state, “we have not only identified NPC1L1 as an HCV cell entry factor but also discovered a new antiviral target and potential therapeutic agent.”

Source

Hepatitis C warning for HIV-positive men

doctor

Most people experience no symptoms in the first six months after infection with hepatitis C

by Stephen Grayfor PinkNews.co.uk
27 January 2012, 3:39pm

A new report is calling for raised awareness of the risks posed by hepatitis C to gay men living with HIV.

The National AIDS Trust said the implications of hepatitis C and HIV co-infection on health can be severe, with liver disease one of the major causes of serious illness and fatality in HIV-positive people.

According to the Trust’s report, 7% of HIV positive gay men are co-infected with hepatitis C. In most cases, no symptoms are experienced after infection.

Generally, about 25% of people infected with hepatitis C clear the virus naturally from their blood during acute infection but three quarters will go on to develop chronic hepatitis C, which targets the liver.

And of those who successfully clear hepatitis C through treatment, a significant percentage are re-infected within a short time.

The charity said infections among gay men are largely due to sexual risk factors, thought to include unprotected anal sex, fisting, use of sex toys, group sex and said drug use may also have a role.

The report criticises the lack of an explicit national strategic approach to tackling this issue and says the stigma around hepatitis C in the gay community and amongst people with HIV hampers prevention efforts and harms gay men.

Deborah Jack, Chief Executive of NAT, said: “The rate of HIV-positive gay men co-infected with hepatitis C in the UK is too high. It is crucial for this to be addressed as a strategic priority in gay men’s health promotion.

“It is vitally important that, as recommended, all people diagnosed with HIV are annually screened for hepatitis C infection and this should be made a requirement in the commissioning of all relevant services (in a recent audit only 66% had had an annual test). Clinics and health promoters need to provide intensive advice and support to gay men at significant risk of hepatitis C transmission. To that end, consensus is urgently needed on the key risk factors for sexual transmission so clear and appropriate recommendations can then be made.

“We also strongly urge gay men not to rely on their sexual partners’ disclosure of their HIV or hepatitis C status as a high proportion are unaware they are infected, which is certainly fuelling onward transmission. And even when diagnosed, disclosure can be difficult – we need to start challenging hepatitis C stigma as well as HIV stigma – both are unfair, ill-informed and destructive.”

Symptoms which do occur in the initial ‘acute’ stage of hepatitis C, which lasts for about six months after infection, include diarrhoea, nausea and jaundice.

Longer term, about half of people with hepatitis C can experience symptoms such as generally feeling unwell, extreme tiredness, weight loss, intolerance of fatty food, and depression.

The Trust’s report is available here for download as a PDF.

Source

The Effect of Caffeine and Alcohol Consumption on Liver Fibrosis

From Liver International

A Study of 1045 Asian Hepatitis B Patients Using Transient Elastography

Arlinking Ong; Vincent Wai-SunWong; Grace Lai-Hung Wong; Henry Lik-Yuen Chan

Posted: 01/25/2012; Liver International. 2011;31(7):1047-1053. © 2011 Blackwell Publishing

Abstract and Introduction
Abstract

Background: Role of caffeine consumption in chronic hepatitis B virus (HBV)-infected patients and the interaction with alcohol consumption is unclear.
Aim: This study aimed to investigate the relationship between caffeine and alcohol consumption and liver stiffness in chronic HBV-infected patients.
Methods: Chronic HBV-infected patients who underwent transient elastography examination in 2006–2008 were studied. Advanced fibrosis was defined as liver stiffness >9 kPa for patients with normal alanine aminotransferase (ALT) or >12 kPa for those with elevated ALT according to previous validation study. Caffeine and alcohol consumption was recorded using a standardized questionnaire. Excessive alcohol intake was defined as 30 g/day in men and 20 g/day in women.
Results: The liver stiffness of 1045 patients who completed the questionnaire was 8.3 ± 6.2 kPa. Two hundred and sixteen (20.7%) patients had advanced fibrosis. Ninety-five (19.0%) patients who drank ≥1 cup of coffee had advanced fibrosis, compared with 121 (22.2%) patients who drank <1 cup (P=0.21). The amount of caffeine intake had positive correlation with the amount of alcohol intake (rs=0.167, P<0.001). Although 231 (22.1%) patients reported alcohol consumption, only 11 (1%) had excessive alcohol intake. The prevalence of advanced fibrosis among patients with mild to moderate alcohol intake (26, 18.8%) was comparable to that among non-drinkers (190, 21.0%) (P=0.57).
Conclusion: Caffeine intake does not affect liver stiffness in chronic HBV-infected patients. Patients who drink coffee regularly tend to drink alcohol. Most chronic HBV-infected patients do not have excessive alcohol consumption. The prevalence of advanced fibrosis among mild to moderate alcohol drinkers was low in this population.

Introduction

Chronic hepatitis B virus (HBV) infection is a global health problem affecting over 350 million people. Persistent hepatic inflammation because of chronic HBV infection will result in progressive liver fibrosis, which will eventually result in cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC).[1]

Alcoholism[2] is a primary chronic disease with genetic, psychosocial and environmental factors influencing its development and manifestations. Heavy alcohol consumption commonly causes alcoholic liver disease, cirrhosis and even HCC.[3] However, it is unclear whether consumption of a smaller amount of alcohol is safe in chronic hepatitis B patients.

On the other hand, consumption of coffee or caffeine may reduce liver injury. Greater coffee, and especially caffeine, intake was associated with a lower prevalence of abnormal alanine aminotransferase (ALT) activity in USA[4] and Japan.[5] Plasma glutathione was increased by 16% on coffee consumption in an Italian population.[6] In a prospective study among advanced Hepatitis C-related liver disease, regular coffee consumption was associated with lower rates of disease progression.[7] In human hepatoma cell lines, coffee and its major components (caffeine, cafestol and kahweol) alter expression and activity of enzymes involved in xenobiotic mechanisms.[8] Mice pretreated with cafestol and kahweol were protected from carbon tetrachloride toxicity by inhibiting cytochrome CYP 2E1,[9] an enzyme responsible for carbon tetrachloride bioactivation while caffeine specifically inhibited expression of connective tissue growth factor by interfering with transforming growth factor-β signaling through the SMAD pathway and upregulate peroxisome proliferator activated receptor γ levels. These in vitro and in vivo data suggested that caffeine has antifibrotic effects.[10]

A recent case control study among chronic hepatitis B carriers showed that coffee consumption reduced the risk of HCC by half with a significant dose-response effect.[11] It is uncertain if the beneficial effect is mediated through prevention of liver fibrosis and cirrhosis. In the past, large-scaled studies on risk factors of liver fibrosis and cirrhosis were difficult to conduct because the assessment required liver biopsy, which was invasive and not acceptable by all patients. In this study, we aimed to determine the effect of alcohol and caffeine consumption on the prevalence of advanced liver fibrosis among chronic HBV-infected patients using transient elastography.

Methods
Study Population

We prospectively recruited chronic HBV-infected patients regardless of the disease activity for transient elastography. We received referrals from all primary care and hospital clinics in Hong Kong from July 2006 to February 2008.[12] Chronic HBV infection was diagnosed by positive serology tests for serum HBsAg for at least 6 months. We excluded patients with evidence of other chronic liver disease by screening with antibody against hepatitis C virus, antinuclear antibody, antismooth muscle antibody, antimitochondrial antibody, serum ceruloplasmin, transferrin saturation and ferritin.

From April to May 2008, patients from the original cohort were phone-interviewed with a verbal consent for this study. Questions concerning their alcohol and caffeine consumption (days per week of consumption and amount per day) in the previous year were asked from a standardized questionnaire. Patients who refused to give verbal consent for the phone-interview were not included in this study.

Clinical Evaluation

All patients received comprehensive clinical and laboratory assessment at the time of transient elastography. Serum HBV DNA levels were measured by the TaqMan real-time polymerase chain reaction assay with a range of detection from 100 to 109 copies/ml.[13] Anthropometric parameters including body weight, body height, hip circumference and waist circumference were measured. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared. Overweight was defined as BMI≥23 kg/m2, and obesity as BMI≥25 kg/m2 according to the Asian and Chinese criteria.[14] We defined moderate and severe obesity as BMI≥28 kg/m2 M and ≥30 kg/m2 respectively. Excessive alcohol intake was defined as >30 g/day in men and >20 g/day in women.[15]

Liver Stiffness Measurement by Transient Elastography

Transient elastography (FibroScan®, Echosens, Paris, France) is one of the new noninvasive modality to evaluate liver fibrosis by measuring liver stiffness. It uses an ultrasound-based technique to measure the speed of propagation of the shear wave through the liver. It can assess approximately 1/500 of the liver's total mass thus reducing the sampling error. Transient elastography has been shown to accurately predict histological advanced fibrosis in different liver diseases.[16–21]

Liver stiffness measurement (LSM) was performed using transient elastography according to the instructions of the manufacturer. Details of the technical background and examination procedure was described previously.[22] Officially trained operators who had performed at least 50 measurements prior this study were responsible to perform the LSM for the patients who had kept fast for at least 8 h. The LSM was considered reliable only if 10 successful acquisitions were obtained, an interquartile range (IQR)/LSM of ≤30% and the success rate was ≥60%. Liver stiffness was expressed in kPa. We defined advanced fibrosis as liver stiffness >9 kPa for those with normal ALT or >12 kPa for those with elevated ALT (F3 fibrosis on histology).[23,24]

Hui's Index

Hui's index was a non-invasive model comprising of BMI, platelet count, serum albumin and total bilirubin [predictive probabilities=exp(3.148+0.167 × BMI+0.088 × bilirubin [μM]−0.151 × albumin [g/L]−0.019 × platelet [109/L])/(1+exp(3.148+0.167 × BMI+0.088 × bilirubin [μM]−0.151 × albumin [g/L]−0.019 × platelet [109/L]))] to predict significant fibrosis (F2 fibrosis on histology).[25] Among 235 chronic hepatitis B patients with liver biopsy, at a cutoff value of 0.15, the sensitivity, specificity, positive and negative predictive values for significant fibrosis were 93, 49, 41 and 95% respectively.

Phone-interview and Questionnaire

A structured questionnaire interview was conducted over the phone to collect data on alcohol and caffeine intake. Participants were specifically asked about the average quantity and frequency of beer, wine, or liquor consumption to estimate the amount of alcohol consumption. The average quantity and frequency of consumption of coffee (regular, instant, ground and decaffeinated), tea (any kind), cola-type soda (regular or decaffeinated) and chocolate (including chocolate milk) was also enquired to estimate the amount of caffeine consumption. Effect of alcohol and caffeine consumption was analyzed with respect to the severity of liver fibrosis as assessed by transient elastography, Hui's Index and other clinical and biochemical parameters

Statistical Analyses

Total caffeine consumption (mg/day) was estimated by summing caffeine from regular coffee (137 mg per cup), regular tea (47 mg per cup), regular and diet cola-type soda (46 mg per bottle or can) and chocolate (7 mg per serving).[26] As for the coffee cup equivalent, the total caffeine consumption per day was divided by 137 (Table 1). Continuous variables were expressed in mean ± standard deviation or median (IQR) as appropriate. Qualitative and quantitative differences between subgroups were analyzed using χ2 or Fisher's exact test for categorical parameters as appropriate, and Student's t-test or Mann–Whitney test for continuous parameters as appropriate. Logistic regression analyses were performed to determine if caffeine and alcohol consumption was associated with liver fibrosis. The multivariate adjusted logistic regression model included covariates that were included in univariate analysis. Spearman's rank correlation was used to correlate caffeine and alcohol intake. All statistical tests were two-sided. Statistical significance was taken as P<0.05. Statistical analysis was performed by Statistical Package for Social Science (SPSS version 17.0, Chicago, IL, USA).

Results
Patient Characteristics

Overall, 22.7% of 1532 patients in this study came from primary care clinics and 77.3% were from hospital clinics. Six patients were excluded because of anti-HCV positivity, 60 patients because of unreliable LSM results and 421 as we failed to contact for phone-interview because of various reasons (e.g. changed telephone numbers or no answer despite multiple attempts). For patients we able to contact via phone, none of them refused to give verbal consent for the phone interview. A total of 1045 chronic hepatitis B patients were thus included in this study. Majority of patients were males (652, 62.4%), of which 175 (26.8%) were overweight and 210 (32.2%) were obese. Two hundred forty seven (37.9%) male patients had elevated ALT with 71% having HBV DNA of more than 4 logs copies/ml. Four hundred and ninety-nine (47.8%) patients consumed one cup of coffee or more per day, while 231 (22.1%) patients drank alcohol. Only 26 (2.5%) patients reported no intake of both coffee and alcohol. The median (IQR) daily consumption of caffeine from food and beverages was 124 (51.6–275.6) mg/day or 1 (0.4–2.0) cup of coffee/day while alcohol consumption of >20 g/day was 1.9% (Table 2). Two hundred and sixteen (20.7%) patients had LSM suggestive of advanced fibrosis.

Caffeine Intake and Liver Fibrosis

Table 3 shows the median total caffeine consumption in mg/day and the coffee cup equivalent according to different patient characteristics where there was no significant difference in caffeine consumption among those with no fibrosis and advanced fibrosis. There was no significant difference in LSM (Table 4). In addition, caffeine intake had no significant correlation with liver stiffness (rs=0.011, P=0.722) or the Hui's index (rs=−0.002, P=0.948). Based on LSM and the Hui's index, caffeine intake by univariate and multivariate analysis was not associated with the risk of advanced liver fibrosis (Table 5).

Alcohol Intake and Liver Fibrosis

Majority of patients (77.9%) did not consume alcohol while only 11 out of 231 patients with alcohol consumption had excessive alcohol drinking. The highest alcohol consumption per day was 88 g. Advanced fibrosis was only prevalent in 26 (18.8%) of those with mild to moderate alcohol consumption compared with 190 (21.0%) of those non-alcoholic drinkers (P=0.57).

Those who drink alcohol have significantly higher caffeine consumption than those who do not drink alcohol (Table 3). Caffeine intake had positive correlation with alcohol intake (rs=0.167, P<0.001).

Discussion

In this large territory-wide observational study with prospective recruitment, we assessed the relationship between caffeine and alcohol consumption and the risk of advanced liver fibrosis in chronic hepatitis B patients with different disease severity. Caffeine intake was not associated with advanced fibrosis. Patients who drank coffee regularly were more likely to consume alcohol. On the other hand, few chronic hepatitis B patients in Hong Kong had excessive alcohol consumption. Mild to moderate alcohol consumption did not increase the risk of advanced fibrosis.

Coffee is a rich source of a number of phenol compounds with antioxidant effects in vitro, with main polyphenols are phenolic acids such as chlorogenic and caffeic acid.[27] Caffeine and its metabolites, 1-methylxanthine and 1-methyluric acid, have also been shown to have antioxidant properties.[28] Caffeine has also been reported to inhibit chemical carcinogenesis and ultraviolet B light induced carcinogenesis in mice.[29,30] Coffee is also found to decrease the progression of liver disease among those with advanced hepatic fibrosis[7] and even reduce the risk of HCC[31,32] One study[33] concluded that approximately 2 coffee cup equivalents/day was associated with less severe hepatic fibrosis, but the beneficial effect was only shown in patients with chronic hepatitis C rather than patients with other liver diseases. A case control study in Italy showed that the protective effect of coffee on HCC was mainly in people who are not chronically infected with HBV.[31] Overall, previous studies included mostly chronic hepatitis C patients and HBV patients were underrepresented. Based on our results, it appears that liver fibrosis in chronic hepatitis B patients is determined mainly by virological and genetic factors and less affected by caffeine intake.

In previous reports, men who have daily alcohol intake of 30–39 g and women who consumed 20–29 g of alcohol daily would have an increased risk of all cause mortality among the general population.[34] Seventy-eight percent of our cohort did not drink alcohol at all while only 1% of patient had history of excessive alcohol consumption. Nonetheless, we could not find any deleterious effect of mild to moderate alcohol consumption to liver fibrosis. As alcohol drinkers were mostly coffee drinkers as well, the concomitant caffeine intake might but one of the confounders leading to the absence of increased risk of advanced fibrosis in alcohol drinkers. Nonetheless only a minority (1% of the study population has excessive alcohol intake, we believe that the major reason of the absence of increased risk of advanced fibrosis in alcohol drinkers was the modest instead of excess amount of alcohol use. Because most of our patients had no advanced liver disease as compared with other studies (33, 35–38), our results could not be extrapolated to cirrhotic patients. Less than 20 g of alcohol intake tends not to increase risk of advanced fibrosis in our present study. Controlled prospective studies may be done in the future to verify this.

One of the limitations of our study was the lack of liver biopsy. As liver biopsy is an invasive procedure, studies using histological fibrosis as an endpoint might suffer from the problem of small sample size and selection bias towards patients with active or advanced liver disease.[39] On the other hand, a non-invasive test such as transient elastography could be applied to a large number of patients with different disease severity. In fact, transient elastography has been shown to be highly accurate in detecting histological advanced fibrosis and cirrhosis in chronic hepatitis B patients,[16,23] though the accuracy might be limited in settings of grossly elevated transaminase levels,[16] but not in the presence of steatosis.[18] Secondly, recall bias might occur during the questionnaire survey and affect the accuracy of the measurement of the caffeine intake measured. We have tried to minimize this bias by using a quantity-frequency questionnaire, which has been previously adapted in a study demonstrating the protective effect of coffee consumption from HCC.[11] There were 159 (15.2%) participants drinking >2–3 coffee-cup equivalents/day and 103 (9.9%) drinking >3 coffee-cup equivalents/day. Because the above numbers for these groups were low and previous finding showing 2 coffee-cup equivalents/day was associated to less severe liver fibrosis, we combined these groups for analysis. Because this is a cross sectional study, possible unmeasured as well as poorly measured confounding factors that may affect the interpretation of our data such as changes in the drinking habit of the patients, variability of caffeine intake over time, socioeconomic status, educational level were not considered in our analysis.

In conclusion, cross-sectional caffeine intake does not affect liver stiffness in chronic HBV-infected patients. The protective effect of caffeine on HCC demonstrated in previous studies is probably via the pathway other than reducing liver fibrosis. The prevalence of advanced liver fibrosis is low (20%) in chronic hepatitis B patients with daily alcohol consumption below 20 g.

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  23. Chan HL, Wong GL, Choi PC, et al. Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B. J Viral Hepat 2009; 16: 36–44.
  24. Wong GL, Wong VW, Choi PC, Chan AW, Chan HL. Development of a non-invasive algorithm with transient elastography (Fibroscan) and serum test formula for advanced liver fibrosis in chronic hepatitis B. Aliment PharmacolTher 2010; 31: 1095–103.
  25. Hui AY, Chan HL, Wong VW, et al. Identification of chronic hepatitis B patients without significant liver fibrosis by a simple noninvasive predictive model. Am J Gastroenterol 2005; 100: 616–23.
  26. Michels KB, Willett WC, Fuchs CS, Giovannucci E. Coffee, tea, and caffeine consumption and incidence of colon and rectal cancer. J Natl Cancer Inst 2005; 97: 282–92.
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  28. Lee C. Antioxidant ability of caffeine and its metabolites based on the study of oxygen radical absorbing capacity and inhibition of LDL peroxidation. Clin Chim Acta 2000; 295: 141–54.
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Statins May Stave Off Liver Cancer in People With Hepatitis B

Hepatitis_02

Study found lower risk of developing disease for people taking these cholesterol-cutting drugs.

Last Updated: January 26, 2012.

By Denise Mann
HealthDay Reporter

THURSDAY, Jan. 26 (HealthDay News) -- Popular cholesterol-lowering statins may also lower risk for liver cancer among people with hepatitis B, a new study shows. Hepatitis B, an inflammation of the liver due to the hepatitis B virus, is one of the main causes of liver cancer.

This is not the first time that statins have shown promise in reducing risk for cancer. Other studies have hinted that these drugs may play a role in preventing certain types of cancer, including breast cancer.

In the new study of more than 33,000 individuals with hepatitis B followed from 1997 to 2008, those who took a statin were less likely to develop liver cancer, when compared to participants who were not prescribed statins. What's more, the longer a person took statins, the greater the liver-cancer risk reduction. Study participants were prescribed the statins to treat high cholesterol levels. Overall, 1,021 people developed liver cancer during the study period.

More research is needed to see how statins may lower liver cancer risk among people with hepatitis B, the researchers said.

"Statins have potential protective effects against cancers [and] carriers of hepatitis B virus infection have a substantial risk of [liver] carcinoma," said Dr. Pau-Chung Chen, a professor of environmental medicine and epidemiology at National Taiwan University, in Taipei. "Statin use is not only a benefit to preventing cardiovascular diseases, but also an additional, convenient and acceptable strategy for preventing hepatocellular carcinoma," or liver cancer, Chen said.

However, statins can cause a potentially dangerous rise in liver enzymes and liver damage. Regular liver function tests are required for all people who take statins.

The study appeared online Jan. 23 in the Journal of Clinical Oncology.

"This is exciting and unequivocally solid research," said Dr. Eugene Schiff, a professor of medicine and director of the Center for Liver Diseases at the University of Miami Miller School of Medicine.

"One of the issues is that statins are relatively contraindicated in people with liver disease," Schiff said. But "the take-home message for people with hepatitis B or anybody with liver disease is that statins are safe. This re-emphasizes the point that if someone has chronic hepatitis B and there is an indication for statins, they should get them and they may be beneficial far beyond lowering cholesterol: They may also reduce their risk for liver cancer."

Dr. David Bernstein, chief of hepatology at North Shore University Hospital and Long Island Jewish Medical Center in Manhasset, N.Y., is more cautious. "In almost all other liver conditions, cirrhosis must be present before [liver cancer] develops," he said. During cirrhosis, scar tissue replaces healthy liver tissue. "Statins must be used with caution in patients with cirrhosis, which can limit their use in patients with liver disease at risk of developing liver cancer," he said. "Further studies are needed in this patient population to confirm these findings."

More information

For information on hepatitis B, visit the U.S. National Digestive Diseases Information Clearinghouse.

SOURCES: Pau-Chung Chen, M.D., professor, environmental medicine and epidemiology, National Taiwan University, Taipei; Eugene R. Schiff, M.D., professor of medicine and director, Center for Liver Diseases, University of Miami School of Medicine; David Bernstein, M.D., chief, hepatology, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, N.Y.; Jan. 23, 2012, Journal of Clinical Oncology, online

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Bedside liver test

doi:10.1038/nindia.2012.13; Published online 27 January 2012

Researchers have designed a new bedside test that can detect signs of harmful diseases in bloodless abdominal fluids within a few minutes1. This will be a useful tool for diagnosing malignant liver disease and diseases that affect other organs.

Abdominal fluids are classified as exudates (rich in protein and cellular elements, oozing out of blood vessels due to inflammation) or transudates (filtrate of blood that accumulates in tissues outside blood vessels, resulting in edema).

Existing techniques for identifying exudates and transudates are lab-based delaying analysis and therapy. The researchers devised a novel bedside method for classifying exudates and transudates to identify possible signs of disease.

They collected bloodless abdominal fluid samples from patients of tuberculosis, liver and ovarian cancer and cirrhosis of liver. They added hydrogen peroxide to the fluid samples. All the exudates showed profuse bubbles within a minute of this. None of the transudates bubbled, but profuse bubbles were observed when the transudates were mixed with blood or catalase prior to the addition of hydrogen peroxide.

The researchers say that the appearance of profuse bubbles within one minute allows the abdominal fluid to be classified as either an exudate or a transudate without the sample needing to be transported to clinical lab, thus minimizing the time between sample collection and diagnosis.

The authors of this work are from: Department of Biochemistry and Department of Medicine, Calcutta National Medical College, Kolkata, and Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

References

  1. Sarkar, S.et al. Development of a point of care testing tool to classify peritoneal effusion as exudate and transudate. Clin. Chim. Acta. 413, 121-125 (2012)

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HIV Risk Behavior Declining, Family Survey Shows

By Michael Smith, North American Correspondent, MedPage Today
Published: January 26, 2012
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.

Americans appear to be taking fewer chances with HIV, according to the CDC.

Slightly more than 9% of the people surveyed from June 2006 to June 2010 reported behaviors thought to increase the risk of HIV, such as male-to-male sexual contact, illicit drug injection, and higher numbers of opposite-sex partners, according to Anjani Chandra, PhD, and colleagues at the CDC.

That's down from nearly 12% when the same survey was conducted in 2002, Chandra and colleagues said in a report issued by the agency's National Center for Health Statistics.

The year 2011 marked the 30th anniversary of the first diagnosed case of HIV, they noted.

The study found that the proportion reporting at least one of a series of HIV-risky behaviors was down for both men and women, the researchers reported -- a drop that appears to be related to a decline in sexually risky practices.

The findings come from the 2006-2010 National Survey of Family Growth, involving in-person interviews with a national sample of 22,682 men and women ages 15 through 44.

Data from the survey were compared to those obtained during the 2002 family growth survey.

The 2006 to 2010 survey was conducted by trained interviewers who read most questions to participants and entered the answers in a computer.

But, because of its sensitivity, most of the data for the current analysis was obtained through what is called audio computer-assisted self-interviewing, in which a participant listens to questions through headphones or reads them on the screen, or both, and responds directly and privately into the computer.

Participants were asked about sexual risk behavior, drug use, whether they had been treated for a sexually transmitted disease within the previous year, and if a condom was used during their most recent sexual encounter.

The researchers calculated summary statistics for sexual and drug risk behaviors and found that the proportion of participants who reported risky sexual behavior fell from 8.9% on 2002 to 5.6% from 2006 to 2010.

On the other hand, there was no difference in the proportion that reported risky drug behavior -- 1.5% in both surveys.

The proportion that reported any risky behavior fell from 11.9% in 2002 to 9.2% from 2006 to 2010.

Among statistically significant changes:

  • Fewer men and women reported exchanging sex for drugs or money. In 2002, 2.6% of men and 2.0% of women reported such behavior, but that fell to 1.3% and 0.7%, respectively, in the later survey.
  • Fewer reported having a sex partner who injected illicit drugs. In 2002, 2.3% of men and 2.9% of women reported such behavior, but that fell to 0.7% and 0.8%, respectively, from 2006 to 2010.
  • More women reported recent treatment for an STD, while the rate for men was stable at 2.6%. In 2002, the proportion of women reporting treatment was 3.4%, which rose to 4.1% from 2006 to 2010. The change was significant at P<0.05 both when comparing women in the two surveys and versus men from 2002 to 2010.
  • The proportion of men reporting crack cocaine use fell from 1.8% to 0.8%. The proportion of women reporting they used the drug also fell -- from 0.8% to 0.7% -- but the change was not significant.

The researchers cautioned that the study is a "useful snapshot" of the prevalence of risky behaviors, but does not account for factors that might increase or decrease individual risk.

As well, they noted, the study only included people living in a household, so the findings might not apply, for instance, to the homeless or those in institutions.

Finally, they cautioned, the study only included people ages 15 to 44 and the results do not apply to those older or younger, who also may be at risk.

The analysis was conducted by the CDC. Authors are employees of the agency.

Primary source: National Health Statistics Reports
Source reference:
Chandra A, et al "HIV risk-related behaviors in the United States household population aged 15–44 years: data from the National Survey of Family Growth, 2002 and 2006–2010" National Health Statistics Reports 2012; 46.

Source

FDA Supplement Guidance Not Strict Enough, MD Says

By Emily P. Walker, Washington Correspondent, MedPage Today
Published: January 26, 2012

An FDA proposal to require dietary supplement manufacturers to submit data proving their product is safe doesn't go far enough, according to a physician writing in the New England Journal of Medicine.

More than 100 million Americans spend more than $28 billion on vitamins, minerals, herbal ingredients, amino acids and other natural products in the form of dietary supplements each year, "assuming they are both safe and effective," wrote Pieter A. Cohen, MD, of Harvard Medical School and the Cambridge Health Alliance.

But they have no assurance that the products are safe because FDA regulation of supplements is too weak, Cohen wrote in a Perspective piece.

By law, ingredients that were used and sold in supplements prior to 1994 can be marketed without any proof that they are safe or effective. But under a law called the Dietary Supplement Health and Education Act (DSHEA), manufacturers of any ingredient introduced after 1994 must provide the FDA with evidence supporting "a reasonable expectation of safety."

Cohen said that part of the law "has thus far not been enforced."

Since DSHEA became law more than 15 years ago, the number of supplements on the market has gone from 4,000 to more than 55,000. Since 1994, the FDA has received proper notification for 170 new supplement ingredients, "undoubtedly a small fraction of the ingredients for which safety data should have been submitted," Cohen said.

The FDA has mounted a new effort to discourage the sale and use of nutritional supplements that contain ingredients that are regulated as drugs. Last year, the agency issued draft guidance meant to inform supplement manufacturers about what information they must submit to the FDA, including spelling out when an ingredient is considered old and when it's considered new. (A synthetically produced replica of a botanical product, for instance, would be considered new).

In addition, the FDA is proposing that the guidance call for in vitro, animal, and long-term tolerability testing for supplements that would be marketed at higher doses than those historically ingested.

"The FDA's guidance provides a thoughtful framework for evaluating the safety of new ingredients and if implemented it would lead to substantial improvement in safety," Cohen wrote, but he said he didn't think the FDA goes far enough.

He said under the guidance, companies can use historical data (instead of clinical trials) to prove that a supplement is safe, and Cohen said that the FDA can't assess the safety of new products scientifically without experimental data.

Cohen also said that under the guidance, manufacturers would not be required to submit both favorable and unfavorable data to the FDA, so they could cherry-pick only positive data to submit.

The dietary supplement industry largely opposes the draft regulation.

One opponent is the Natural Products Association, whose 1,900 members include small health food stores and large supplement manufacturers. The group submitted its official response to the FDA's proposal in November and said the agency is "overstepping" and that the rules would have a "chilling effect" on the dietary supplement industry.

"The draft guidance as currently written sets up inappropriate barriers to market entry, imposes food additive criteria, and requires multiple ... notifications beyond those required by law," the group wrote.

Cohen said it's true that the proposed requirements would impose similar standards on supplements and food additives.

"Industry advocates are correct insofar as DSHEA does not hold established (pre-1994) supplement ingredients to the same safety standards as food additives: a chemical preservative sprayed inside a can of tomato soup or the purple dye in Jell-O requires much more evidence of safety than ingredients used in supplements," Cohen wrote.

Cohen urged the FDA to not change its proposal because of protests from industry.

"If the FDA succumbs to industry pressure, the public health consequences will be significant, as hundreds of thousands of Americans continue to turn to new supplements to sustain their health and treat their ailments," he said.

The FDA is accepting comments on the draft guidance until Feb. 1.

Cohen reported no financial conflicts of interest, other than having his travel paid for to be a guest on an episode of the Dr. Oz Show that dealt with supplements.

Source

Also See: Dietary supplements' safety regulation: too much or not enough?