July 7, 2010

The Claim: Exposure to Plants and Parks Can Boost Immunity

Christoph Niemann

July 5, 2010

By ANAHAD O’CONNOR

THE FACTS

This time of year, allergies and the promise of air-conditioning tend to drive people indoors.

But for those who can take the heat and cope with the pollen, spending more time in nature might have some surprising health benefits. In a series of studies, scientists found that when people swap their concrete confines for a few hours in more natural surroundings — forests, parks and other places with plenty of trees — they experience increased immune function.

Stress reduction is one factor. But scientists also chalk it up to phytoncides, the airborne chemicals that plants emit to protect them from rotting and insects and which also seem to benefit humans.

One study published in January included data on 280 healthy people in Japan, where visiting nature parks for therapeutic effect has become a popular practice called “Shinrin-yoku,” or “forest bathing.” On one day, some people were instructed to walk through a forest or wooded area for a few hours, while others walked through a city area. On the second day, they traded places. The scientists found that being among plants produced “lower concentrations of cortisol, lower pulse rate, and lower blood pressure,” among other things.

A number of other studies have shown that visiting parks and forests seems to raise levels of white blood cells, including one in 2007 in which men who took two-hour walks in a forest over two days had a 50-percent spike in levels of natural killer cells. And another found an increase in white blood cells that lasted a week in women exposed to phytoncides in forest air.

THE BOTTOM LINE

According to studies, exposure to plants and trees seems to benefit health.

ANAHAD O’CONNOR scitimes@nytimes.com

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Waiting game over

Lauren Gilchrist

Jul 07, 2010 - 4:35 PM

William Catt, who received hepatitis C during a 1976 blood transfusion, has received his final payment of $1,200 from the Federal government
 
(PETERBOROUGH) The waiting game is over for William Catt.

After 35 years of living with hepatitis C he has received a final settlement payment of $1,200 from the federal government.

But Mr. Catt says that's just not acceptable considering the virus has ruined his life. Now he has to decide whether he will sign the papers and end more than three decades of trying to fight for what he believes is fair, which he says amounts to more like $80,000. But he doesn't have any fight left in him.

"I'm just so tired of it," he says, from his home in Baileboro.

Mr. Catt was 17 years old when he underwent a blood transfusion at Humber Memorial Hospital. It was 1976 and there was no screening process in place for donated blood. The operation was supposed to help him cope with Crohn's disease, but instead he contracted hepatitis C.

"I went in with crones disease and came out with Crohn's disease and tainted blood," he says.

Now 52 years old and taking some 60 pills a day, Mr. Catt says between the Crohn's and the hepatitis C he hasn't been able to work for the last 25 years. To date he has received a total of $25,000 in compensation from the Canadian Red Cross and $10,000 from KPMG, a company that administers claims relating to hepatitis C pursuant to settlements with the Canadian Red Cross Society. Although he receives disability payments he says the $80,000 he wanted would have helped him out an awful lot.

In 2006, the federal government announced hepatitis C victims who were excluded from the previous compensation package handed out in 1998 will share $1.1 billion in funding. This compensation directly involves Mr. Catt since he is one of the people who contracted the virus before 1986. Payments ranged anywhere from $30,000 to $250,000 depending on the severity ranging from level one to six, with level six being the most severe. Mr. Catt says he was classified as level one, but he tried to have his case classified as a level two, which he says would have entitled him to something around the lines of $80,000. To make matters worse, Mr. Catt says last week a doctor at Toronto Western Hospital told him he no longer has hepatitis C, a claim he doesn't believe.

Mr. Catt says at $35,000 he hasn't received his fair share. He says if he had received the $80,000 he would have turned around and given back the Red Cross $25,000. He says the federal government has let him down.

"I'm going to settle for the $1,200. I don't want to do that, I want the $80,000 I requested," he says.

"It's getting too much on me."

Source

Action Plan for Liver Disease Research


Liver disease is an important cause of morbidity and mortality in the United States, affecting persons of all ages, but most frequently individuals in the productive years of life, between the ages of 40 and 60 years. Liver disease also disproportionately affects minority individuals and the economically disadvantaged. Medical research on liver disease is critically important and further progress in research promises to bring under control the major toll of liver disease on human health and well-being. Indeed, the last 25 years of medical research in liver disease has resulted in major improvements in the survival and quality-of-life of patients with liver disease. The next 25 years should bring even more profound and important changes.

To address the burden of liver diseases in the United States, the National Institutes of Health has developed an Action Plan for Liver Disease Research.

Mission Statement
The goal of the Action Plan for Liver Disease Research is to advance research on liver and biliary diseases with the aim of decreasing the burden of liver and biliary diseases in the United States.

The Action Plan for Liver Disease Research is available in both electronic (PDF) and print formats.Electronic versions (PDF): The Action Plan for Liver Disease Research can be downloaded from this website by clicking on the following files, which contain separate sections of the Plan. These files are in PDF format, which requires the free Adobe Acrobat® Reader for viewing. 
Print:
Free single copies (no bulk orders) of the Action Plan are available from the:
National Digestive Diseases Information Clearinghouse
2 Information Way
Bethesda, MD 20892-3570
(Please use 9-digit ZIP code.)
Phone: 1-800-891-5389Fax: 703-738-4929
Email: nddic@info.niddk.nih.gov
(Please include your name, mailing address, telephone, and email address.)

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Hepatology June 2010

"None of the SVR patients developed EV compared with 22 (31.8%) of the 69 untreated subjects (P < 0.0001) and 45 (39.1%) of the 115 non-SVR patients (P < 0.0001).....

in the long term, the achievement of SVR prevents the development of EV in patients with compensated HCV-induced cirrhosis. Therefore, in these patients, endoscopic surveillance can be safely delayed or avoided. Genotype 1b infection and MELD score identify the subset of patients at higher risk of EV development who need tailored endoscopic surveillance......even if there is growing evidence that antiviral treatment may reduce the rate of complications related to portal hypertension when leading to SVR, no study has evaluated whether viral eradication could prevent EV development in the long term......A major finding of our study - and one of great importance in clinical practice - is that the achievement of SVR abolishes the development of EV in the long term. The reliability of our result is guaranteed by the ample length of observation among this group of patients (median follow-up after initiation of antiviral therapy being 12 years)."

Savino Bruno 1 *, Andrea Crosignani 2, Corinna Facciotto 1, Sonia Rossi 1, Luigi Roffi 3, Alessandro Redaelli 4, Roberto de Franchis 5 6, Piero Luigi Almasio 7, Patrick Maisonneuve 8 1Department of Internal Medicine, A.O. Fatebenefratelli e Oftalmico, Milan, Italy 2Department of Internal Medicine, A.O. S. Paolo 3A.O. Sondrio, Italy 4Endoscopy Unit, A.O. S. Gerardo, Monza, Italy 5Gastroenterology and Gastrointestinal Endoscopy Unit, Ospedale Policlinico, Milan, Italy 6Department of Medical Sciences, University of Milan, Milan, Italy 7Gastroenterology and Hepatology Unit, University of Palermo, Palermo, Italy 8Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy

Abstract

The incidence of de novo development of esophageal varices (EV) in patients with compensated liver cirrhosis has been determined by few studies in the short term and never in the long term. The aims of the present study were to determine the incidence and the risk factors associated with the development of EV and to assess whether antiviral treatment and achievement of sustained virologic response (SVR) may prevent de novo EV development in patients with HCV-induced cirrhosis. We studied 218 patients with compensated EV-free, HCV-induced cirrhosis consecutively enrolled between 1989 and 1992 at three referral centers in Milan, Italy. Endoscopic surveillance was performed at 3-year intervals according to international guidelines. SVR was defined as undetectable serum HCV-RNA 24 weeks after treatment discontinuation. During a median follow-up of 11.4 years, 149/218 (68%) patients received antiviral treatment and 34 (22.8%) achieved SVR. None of the SVR patients developed EV compared with 22 (31.8%) of the 69 untreated subjects (P < 0.0001) and 45 (39.1%) of the 115 non-SVR patients (P < 0.0001). On multivariate analysis, HCV genotype 1b (hazard ratio [HR] 2.40; 95% confidence interval [CI] 1.17-4.90) and baseline model for end-stage liver disease (MELD) score (HR 1.20; 95% CI 1.07-1.35 for 1 point increase) were independent predictors of EV. Conclusion: In the long term, the achievement of SVR prevents the development of EV in patients with compensated HCV-induced cirrhosis. Therefore, in these patients, endoscopic surveillance can be safely delayed or avoided. Genotype 1b infection and MELD score identify the subset of patients at higher risk of EV development who need tailored endoscopic surveillance.

The natural history of patients with compensated liver cirrhosis, induced by hepatitis C virus (HCV) is now well characterized.[1-5] However, even if it is well established that the onset of esophageal varices (EV) marks a crucial turning point in the outcome of the disease,[6] only one study has assessed the incidence of de novo development of EV prospectively over a short period. However, this study combined patients with alcoholic, HCV-related, hepatitis B virus-related and cryptogenic cirrhosis.[7] In addition, the effect of antiviral therapy and the achievement of sustained virologic response (SVR) on EV development has never been evaluated. Finally, apart from the level of the hepatic vein pressure gradient (HVPG), which has recently been shown to be associated with the risk of EV development,[7] no other reliable predictor of EV has been described.

The availability of a large prospective cohort study[5] that included consecutive patients with compensated HCV-induced cirrhosis followed for up to 18 years allowed us to evaluate the incidence of, the risk factors associated with, and the impact of antiviral treatment, including the effect of SVR, on de novo development of EV in the long term.

Abbreviations

CI, confidence interval; EGD, esophago-gastro-duodenoscopy; EV, esophageal varices; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; HVPG, hepatic vein pressure gradient; IFN, interferon; MELD, model for end-stage liver disease; SVR, sustained virologic response.

Discussion

In recent years, several studies have described disease outcomes in patients with compensated HCV-induced cirrhosis.[1-5] However, although these investigations provide relevant information, none of them report data about the de novo development of EV. In addition, even if there is growing evidence that antiviral treatment may reduce the rate of complications related to portal hypertension when leading to SVR, no study has evaluated whether viral eradication could prevent EV development in the long term.

The present investigation, which fulfills the quality criteria requirements for both observational[20] and subgroup analysis studies,[8] provides several important data. First, it provides an accurate estimate of the 10-year cumulative incidence of EV in this population of patients. Our figures are lower than those recently reported by Groszmann et al.[7] in a 5-year follow-up study. This discrepancy could be easily explained by the different characteristics of patients included in the two studies. In the latter study, more than one third of subjects had nonviral cirrhosis (predominantly alcohol-related), 12% had more advanced disease (Child-Pugh score B), all patients with hepatitis B virus-induced disease did not assume antiviral therapy, and the timing of endoscopic surveillance between studies was different (every 3 years, as suggested by the international guidelines in clinical practice, instead of annually). Moreover, a high proportion of the patients included in the study by Groszmann et al. had a high HVPG (63% had at least 10 mm Hg, with a median of 11 mm Hg). By contrast, the majority of our patients had the diagnosis of cirrhosis made by liver biopsy at the time of enrollment (i.e. at an early, less severe stage of the disease). On the other hand, it is well-established that the stage of compensated cirrhosis is extremely heterogeneous because it includes patients with different but still unrevealed clinical conditions. Moreover, approximately 20% of our patients did not agree to fulfill the planned schedule of endoscopic surveillance and this fact might have led to underestimation of the rate of EV detection.

A major finding of our study - and one of great importance in clinical practice - is that the achievement of SVR abolishes the development of EV in the long term. The reliability of our result is guaranteed by the ample length of observation among this group of patients (median follow-up after initiation of antiviral therapy being 12 years).

The biological plausibility of our result was supported by the finding that HVPG decreased over the years in the four SVR patients who agreed to undergo this procedure and, in all of them, the HVPG values reached the threshold level (<10 mm Hg), which has been reported to be protective for EV development (data not shown). These data are also supported by other studies in which the achievement of virological response following antiviral therapy was associated with a significant decrease of HVPG values,[21][22] fibrosis regression,[23][24] and reduction of portal hypertension-related complications in patients with similar clinical characteristics.[25][26]

This study failed to identify a reliable predictor associated with high risk for early EV development. This was due to the low incidence of events in the first 3 years of follow-up. However, we found that a higher MELD score at entry and HCV genotype 1b infection are independent predictors of EV development in the long-term. Whereas the higher risk of EV in patients infected with genotype 1b could be attributable to the low rate of SVR in these patients, the statistically significant association in multivariate analysis suggests that genotype 1b may induce a faster progression of portal hypertension as suggested by a recent meta-analysis.[27]

Together with an HVPG value 10 reported by Groszmann et al.,[7] HCV genotype and MELD score may be easily used to identify subjects in whom more frequent, tailored EGD surveillance is warranted.

Another finding emerging from this study is that the risk of EV development increases once HCC has occurred. This result reveals a limitation in our study, however, because frequency of EGD surveillance was performed at 3-year intervals, whereas ultrasound screening for HCC was performed every 6 months. Therefore, we cannot exclude that some patients had developed EV before the emergence of HCC and that the observed rates of EV after the diagnosis of HCC have been overestimated.

In conclusion, the 10-year cumulative incidence of de novo EV in EV-free patients with compensated Child-Pugh class A HCV-induced cirrhosis is fairly low. Despite the presence of established cirrhosis, achievement of SVR after antiviral therapy prevents the development of EV in the long-term. In routine clinical practice, serial surveillance by EGD can be safely delayed or avoided in SVR patients, sparing significant amount of useless invasive and costly procedures. It is conceivable that, as a result of new promising therapies,[28] the rate of SVR in patients with chronic hepatitis C will further increase and the burden of portal hypertension-induced complications will decrease over time. Finally, the evidence that genotype 1b infection and higher MELD score increases the risk of EV indicates that tailored, more frequent endoscopic surveillance in this subset of patients may be warranted.

Results

Among the 352 patients included in the original study,[5] 26 did not agree to undergo EGD at the time of enrollment, and 54 had EV at baseline. In the remaining 272 patients free of varices at baseline, 54 (19.9%) did not adhere to the endoscopic surveillance program and were thus excluded from the present study (Fig. 1). The baseline characteristics of the 218 patients included in the study, stratified according to antiviral treatment and response to therapy, are shown in Table 1.

One hundred sixty-three patients (74.8%) had a diagnosis of cirrhosis obtained by way of liver biopsy at the time of inclusion in the study. Half of them were males (50.9%), the majority infected with HCV genotype 1b (61.5%). Approximately one quarter of patients admitted an excess of alcohol consumption during their life. Treated patients were significantly younger, were less likely to be past heavy alcohol drinkers, and had a lower MELD score compared with untreated ones. Among treated patients, only HCV genotype and baseline alpha-fetoprotein serum levels were associated with SVR (Table 1).

Cumulative Incidence of EV.

During a median follow-up of 11.4 years, de novo EV were detected in 67 patients, at the same frequency in untreated 22/69 (31.8%) and treated 45/115 (31.8%) patients. Overall, eight patients developed EV during the first 3 years of follow-up. At the time of detection, the size of EV was small (F1) in 51 (76.1%) patients, medium (F2) in eight (11.9%) patients, and large (F3) in eight (11.9%) patients. Only one of the eight patients with F2 varices but five of the eight patients with F3 varices bled at the time of recognition. The median time between enrollment and detection of F3 varices was 8 years (range, 3-17).

By contrast, no single EV was detected among the 34 patients who achieved SVR (P < 0.0001 versus both untreated and non-SVR patients). Of interest, the median duration of follow-up from enrollment to last EGD was 7.5 years for untreated patients, 10.7 years for non-SVR patients, and 15.9 years for SVR patients (P < 0.0001). Among treated patients, the median duration between initiation of antiviral therapy and last EGD was 8.8 years for non-SVR patients and 12.0 years for SVR patients (P = 0.006). The cumulative incidence of EV among treated patients according to response to therapy is shown in Fig. 2.

During follow-up, 16 of the patients who had developed EV subsequently bled at the same rate in untreated and non-SVR treated subjects (Fig. 1)

. Figure 3 provides information on the number of patients, person-years of observations events and the 10-year cumulative incidence of EV in the whole series of patients and stratified according to HCV genotype and MELD score.

Incidence of EV and HCC Development.

During follow-up, 66 patients developed HCC, seven of whom had achieved an SVR (Fig. 1). HCC was diagnosed as a single nodule (<2 cm) in 60% of the cases, and 76% of the patients fulfilled the Milan criteria.[19] In 57 cases (86%), patients were free of varices at the last EGD performed before tumor diagnosis. Following HCC diagnosis, EV were detected in 16 patients (in 12 cases within 3 years of tumor occurrence).

Predictors of EV Development.

On univariate analysis, HCV genotype 1b (hazard ratio [HR] 2.38; 95% confidence interval [CI] 1.23-4.59), history of heavy alcohol consumption (HR 2.00; 95% CI 1.16-3.43), elevated serum creatinine (HR 2.41; 95% CI 1.03-5.66), higher MELD score (HR for 1 point increase 1.21; 95% CI 1.08-1.35), alpha-fetoprotein serum leveln >/= 10 hg/mL (HR 1.99; 95% CI 1.20-3.29) and occurrence of HCC (HR 2.65; 95% CI 1.45-4.86) were associated with development of de novo EV (Table 2). We found no association with platelets, albumin, international normalized ratio, or bilirubin levels at baseline.

On multivariate analysis, HCV genotype 1b and baseline MELD score remained independent predictors of EV (Table 2). When intercurrent events were included in the multivariate model, antiviral treatment in absence of SVR did not show any protective effect on EV development (HR 1.02; 95% CI 0.60-1.72). By contrast, HCC occurrence was associated with an HR of 2.87 (95% CI 1.46-5.64) on the development of EV (Table 2). This latter result was not confirmed when the analysis was restricted to the subset of treated patients (Table 3).

When we limited the analysis to F2 or F3 varices (n = 17), a history of heavy alcohol consumption (HR 5.79; 95% CI 1.99-16.8), higher MELD score (HR for 1 point increase 1.27; 95% CI 1.01-1.58), alpha-fetoprotein serum level >/= 10 hg/mL (HR 2.92; 95% CI 1.09-7.87), and occurrence of HCC (HR 4.32; 95% CI 1.41-13.2) were associated with development of medium or large varices in univariate analysis, whereas MELD score and development of HCC remained independent predictors of EV on multivariate analysis (data not shown).

Patients and Methods

The present study is a subgroup analysis based on data obtained from a large-scale prospective study aimed at evaluating the long-term outcome of patients with compensated HCV-induced cirrhosis, which has been described elsewhere.[5] Briefly, from January 1989 to December 1992, all consecutive patients with compensated Child-Pugh class A cirrhosis who presented at three referral centers in the Milan area (Northern Italy) and tested positive for serum anti-HCV were enrolled. The present study followed the guidelines for subgroup analyses[8] and included only subjects who had agreed to undergo upper endoscopy at the time of enrollment (±6 months) and were found to be EV-free.

The Ethics Committees of all participating centers approved the design of the study.

Patients.

The study includes Child-Pugh class A patients with HCV-related cirrhosis <70 years of age. Patients with bridging fibrosis were excluded. The diagnosis of cirrhosis was based on liver biopsy or on clinical criteria.[9] Patients with concurrent hepatitis B or human immunodeficiency virus infection, and patients who were not willing to attend regular follow-up endoscopy were excluded. Patients with previous episodes of decompensation or with hepatocellular carcinoma (HCC) within 6 months from enrollment were also excluded. Anti-HCV was assessed by first- and second-generation enzyme-linked immunosorbent assay. HCV genotype was determined on frozen sera by nested reverse-transcription polymerase chain reaction of HCV core sequences using type-specific primers[10] and confirmed on fresh sera by INNO-LiPA (HCVII, Innogenetics, Ghent, Belgium). Information on alcohol intake (>60 g/day for women, >80 g/day for men, for at least 5 years) was obtained during baseline interview and confirmed by relatives.

All patients underwent a 3-month run-in period, and a database including demographic, clinical, laboratory, and endoscopic examinations obtained at entry was set up. Endoscopic procedures for EV assessment were performed in each center by three skilled endoscopists. The size of EV was determined at medium insufflation and classified according to North Italian Endoscopic Club score.[11] Child-Pugh score was assessed according to current criteria,[12] whereas the MELD score[13] was retrospectively calculated using the information collected at baseline. international normalized ratio was calculated by conversion of prothrombin time or activity at baseline.

Follow-up.

All patients had a regular follow-up that included clinical, laboratory, and abdominal ultrasound surveillance every 6 months. Examination of the upper gastrointestinal tract was planned at 3-year intervals both for treated and untreated patients, as recommended by international guidelines.[14] Esophago-gastro-duodenoscopy (EGD) was also performed at the initiation of antiviral treatment or when clinically required. Additional EGD surveillance after the diagnosis of HCC was not scheduled, unless patients were eligible for surgical resection. At the time of EV detection, beta-blockers were prescribed to patients with medium or large (F2 or F3) varices, while no prophylaxis was scheduled for those with small (F1) varices.

In order to assess the effect of SVR on portal hypertension progression, the measurement of HVPG was also offered to patients who achieved SVR and agreed to perform this procedure. The first HVPG measurement (Time 0) was made 12 months following discontinuation of antiviral treatment and repeated every 3 years (at the same time as EGD). HVPG was measured according to established recommendations.[15]

Up to 2001, the diagnosis of HCC detected during follow-up was based on histological assessment obtained by fine needle liver biopsy whenever a focal liver lesion was detected on ultrasound examination.[16][17] After 2001, diagnoses were made according to Barcelona Conference criteria.[18]

Treatment of HCV Infection.

Recombinant interferon (IFN)- monotherapy or combination with both IFN and ribavirin were offered over time. IFN monotherapy, at the dose of 3 MIU three times a week, was administered, regardless of HCV genotype, for at least 6 months and for an additional 6-month period in patients who achieved a complete biochemical response. Combination therapy with IFN or pegylated IFN and ribavirin was administered in agreement with international guidelines. SVR was defined as undetectable serum HCV-RNA (<50 IU/mL) 6 months after stopping therapy.

Statistical Analysis.

Continuous variables were compared using the Mann-Whitney test. Fisher's exact test and the Mantel-Haenszel chi-square test for trend were used to assess differences in the baseline characteristics between patients who did and did not receive antiviral treatment and between treated patients who did or did not achieve an SVR. Time-to-event was calculated from the date of enrollment to the date of first detection of EV or to the date of last EGD, or death. The cumulative incidence of EV during follow-up was plotted using the Kaplan-Meier method, and the log-rank test was used to assess difference between strata. When specified, observation time was censored at the time of SVR. All patients were included and the time of observation of SVR subjects was censored when successful antiviral treatment was initiated. This choice was justified by the fact that SVR patients were still HCV-RNA-positive in the same way as untreated and non-SVR treated patients until they started antiviral treatment. Univariate and multivariate Cox proportional hazards regression models were used to identify factors associated with EV development. Intercurrent events such as initiation of antiviral therapy, SVR achievement, or HCC occurrence were set as time-dependent covariables. Analyses were performed with SAS version 8.2 (Cary, NC). All statistical tests were two-sided, and P < 0.05 was considered significant.
 
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Also See
Sustained Response to Antiviral Therapy Prevents Esophageal Varices in Hepatitis C Patients with Cirrhosis
 
SVR Prevents Esophageal Varices in Patients with Cirrhosis

SVR Prevents Esophageal Varices in Patients with Cirrhosis

"data suggest that those with chronic HCV and advanced fibrosis who achieve SVR have reduced clinical outcomes, including variceal bleeding.[9] However, the impact of SVR on the de novo development of varices was not specifically assessed in these analyses and remains unknown......In this issue of HEPATOLOGY, Bruno et al. addressed the impact of SVR on the development of esophageal varices in a subgroup analysis of a large prospective database of subjects with compensated HCV-induced cirrhosis.[17] In this study, consecutive HCV-positive subjects seen between January 1989 and December 1992 with compensated, Child A cirrhosis were screened for varices......Bruno and colleagues concluded that SVR prevents the development of varices and that endoscopic surveillance can be delayed or avoided in these patients.......because beta-blockers used to reduce HVPG do not seem to affect the rate of development of varices,[5] the current study is the first to demonstrate a pharmacologic treatment to reduce (or in this case, eliminate) the development of varices.......Finally, they suggest that a more tailored approach based on HCV genotype, MELD score, and HCC would help indentify those patients without SVR who are at higher risk for developing varices and who would benefit from surveillance endoscopy........Importantly, none of the 34 who achieved SVR developed varices; however, 66 patients developed HCC, including seven who had SVR. Multivariate analysis identified HCV genotype 1b, baseline model for end-stage liver disease (MELD) score, and HCC as independent predictors of the development of varices in nonresponders and those who did not undergo HCV therapy."

Editorial

Long-term effects of sustained virologic response on the development of esophageal varices in compensated cirrhosis: Is the bang worth the buck?

Hepatology June 2010

Richard K. Sterling, M.D., M.Sc. Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University Health System, Richmond, VA email: Richard K. Sterling (rksterli@vcu.edu)

The natural history of compensated cirrhosis in those with chronic hepatitis C virus (HCV) has been well described. In the landmark study by Fattovich et al. of 384 compensated subjects, the 5-year risk of hepatocellular carcinoma (HCC) was 7% and the risk of hepatic decompensation was 18%.[1] Of the 355 patients who remained tumor-free, 65 (18%) developed at least one episode of ascites (8.7%), jaundice (1%), hepatic encephalopathy (1.5%), or variceal bleeding (4%), and the mean time to decompensation was 37 months (range, 3-137). In a more recent study, 131 of 352 (37%) subjects with compensated HCV-induced cirrhosis who were followed for a median of 14.4 years developed decompensation.[2] Of the 77 (59%) subjects who were without HCC, 66 (86%) developed ascites, 22 (28%) developed portal hypertensive bleeding, and 21 (27%) developed hepatic encephalopathy. Importantly, those with varices had twice the rate of decompensation compared to those without varices (65% versus 33%). Therefore, development of portal hypertension seems to be an important predictor of decompensation and increased mortality.[3]

Abbreviations:

HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HVPG, hepatic venous pressure gradient; SVR, sustained virologic response.

The development of varices is one of the hallmarks of significant portal hypertension and the incidence of new varices in those with cirrhosis is <5%/year.[4] In those without varices, the development of varices is related to the severity of underlying liver disease and the presence of increased hepatic venous pressure gradient (HVPG) of more than 10 mm Hg. In the study by Groszmann et al. which examined use of beta-blockers to prevent esophageal varices in patients with stable cirrhosis (62% with HCV) without esophageal varices at baseline, the rate of developing varices was similar between those subjects randomized to Timolol and placebo (42 of 108, 39% versus 41 of 105, 40%) during a mean follow-up of 55 months.[5] Although the majority of varices were small, a few patients in each group developed large varices and subsequently bled. However, varices developed less frequently in those with a baseline HVPG < 10 mm Hg and in those who had less than 10% decrease in HVPG at 1 year.

The potential benefit to HCV therapy, in addition to sustained virologic response (SVR), is improvement in outcomes. Because many treated individuals who achieve SVR do not have significant fibrosis, this benefit may not be realized for several years, if not decades. However, although those with advanced fibrosis have poorer response to current therapy,[6] they also have the most to gain. In support of this, studies have shown that those with advanced cirrhosis who achieve SVR have fewer clinical outcomes including liver failure, variceal bleeding, and HCC[2][7-9] (Table 1).

Table 1. Benefits of Virologic Response on Outcomes in Patients with HCV and Advanced Fibrosis

HALT-C, Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis; HCC, hepatocellular carcinoma; HVPG, hepatic venous pressure gradient; SVR, sustained virologic response; stage 3 or advanced fibrosis = bridging fibrosis and stage 4 = cirrhosis.

The mechanism associated with improved outcomes is presumed to be mainly from reduction in hepatic fibrosis. Poynard and colleagues pooled data on 3010 HCV treatment-na•ve patients from four large clinical trials with pretreatment and posttreatment biopsies. They observed significant improvements in both inflammation and fibrosis in those with SVR (25% improved while 7% worsened) compared to those with nonresponse (17% improved while 21% worsened).[10] Importantly, they found reversal of cirrhosis in 75 of 153 (49%) patients. Similar improvements in histology with SVR have been reported by others as well.[11][12]

In addition to improvements in fibrosis, antiviral therapy may also directly affect HVPG. Rincon et al. studied 20 compensated patients with advanced fibrosis, by using liver biopsy and hepatic pressure measurements before and immediately after therapy with pegylated interferon and ribavirin.[13] They found that all but one patient had a significant decrease in HVPG from baseline following antiviral therapy and that those with SVR had a greater reduction than those with nonresponse. The benefits of reductions in HVPG with SVR were confirmed by Roberts et al. in 47 patients with cirrhosis.[14] Although the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial did not show overall benefit of maintenance interferon,[15] improved clinical outcomes were observed in those with significant viral suppression without SVR.[16] Taken collectively, these data suggest that those with chronic HCV and advanced fibrosis who achieve SVR have reduced clinical outcomes, including variceal bleeding.[9] However, the impact of SVR on the de novo development of varices was not specifically assessed in these analyses and remains unknown.

In this issue of HEPATOLOGY, Bruno et al. addressed the impact of SVR on the development of esophageal varices in a subgroup analysis of a large prospective database of subjects with compensated HCV-induced cirrhosis.[17] In this study, consecutive HCV-positive subjects seen between January 1989 and December 1992 with compensated, Child A cirrhosis were screened for varices. Those with hepatitis B, human immunodeficiency virus, prior history of decompensation, or HCC within 6 months were excluded. Among the 352 patients screened, 218 who were free of varices at baseline and agreed to have follow-up endoscopy were included in the analysis. All 218 subjects had regular follow-up with surveillance ultrasound for HCC every 6 months and endoscopy every 3 years to identify de novo varices. Patients received HCV therapy as determined by current practice at that time, and SVR was defined as negative HCV RNA at 6 months after stopping therapy. The primary endpoints were development of de novo varices or HCC. Of the 218 patients, 149 (68%) received HCV therapy and 23% had SVR. During the median follow-up of 11.4 years, de novo varices developed in 67 patients and was similar in untreated (22 of 69, 32%) and treated (45 of 115, 32%) patients. The distribution of varices were small (F1, 76%) while 12% each had moderate (F2) or large (F3) varices. The median time between enrollment and detection of F3 varices (5 of 8 that bled) was 8 years (range, 3-17). Importantly, none of the 34 who achieved SVR developed varices; however, 66 patients developed HCC, including seven who had SVR. Multivariate analysis identified HCV genotype 1b, baseline model for end-stage liver disease (MELD) score, and HCC as independent predictors of the development of varices in nonresponders and those who did not undergo HCV therapy. There was no association observed with platelet count, albumin, international normalized ratio, or bilirubin with de novo varices.

Bruno and colleagues concluded that SVR prevents the development of varices and that endoscopic surveillance can be delayed or avoided in these patients. Finally, they suggest that a more tailored approach based on HCV genotype, MELD score, and HCC would help indentify those patients without SVR who are at higher risk for developing varices and who would benefit from surveillance endoscopy.

As with any long-term study, there are several caveats. Although they included patients from three centers, their results may not be generalizable to all patients with HCV-induced cirrhosis. Second, because not all patients screened were included and follow-up was not complete in all patients, there may have been a type 1 error. Also, we were not told of concurrent medications that might affect portal pressures and the development of varices. Nevertheless, this is the largest study with the longest follow-up to date that addresses the impact of SVR on the development of esophageal varices.

If these results are confirmed, there are several important implications for future management of cirrhosis in those who achieve SVR. First, this study highlights that those with SVR can still develop HCC and that all subjects with cirrhosis should continue periodic surveillance for HCC according to accepted guidelines.[18] Second, because those with SVR do not develop varices, it may not be necessary to expose these patients to the expense and risks of repeated endoscopies. Third, because beta-blockers used to reduce HVPG do not seem to affect the rate of development of varices,[5] the current study is the first to demonstrate a pharmacologic treatment to reduce (or in this case, eliminate) the development of varices. However, before we get too excited, we must remember that current treatment to achieve SVR in those with cirrhosis is difficult and there are often increased side effects, more cytopenias, and lower response rates than those without cirrhosis.[6][19][20] Therefore, given the cost, both in dollars and resources, the increased side effects, and decreased response rates of HCV therapy, it remains to be determined if the bang is worth the buck in this select group of patients.

Also See
Sustained Response to Antiviral Therapy Prevents Esophageal Varices in Hepatitis C Patients with Cirrhosis
 
Source
SUMMARY: Chronic hepatitis C patients with liver cirrhosis who achieve sustained virological response (SVR) to interferon-based therapy are less likely to develop new varices, or swollen veins in the esophagus, according to an Italian study published in the June 2010 issue of Hepatology.

Over years or decades, people with chronic hepatitis C can develop advanced liver disease including cirrhosis and liver cancer. Cirrhosis is characterized by blockage of the flow of blood through the heavily scarred liver, leading to symptoms such as bleeding varicose veins in the stomach and esophagus, abdominal fluid accumulation, and cognitive impairment due to hepatic encephalopathy.

A new study adds to the evidence showing that sustained response to interferon-based antiviral therapy can improve liver health and prevent development or worsening of cirrhosis and its associated conditions, in this case esophageal varices. None of the 34 participants (out of an initial group of more than 200) who were treated for hepatitis C and achieved SVR developed new varices, compared with 32% of untreated patients and 39% of those who underwent treatment but did not achieve sustained response.

Esophageal varices are enlarged veins in the lower esophagus.
They're often due to obstructed blood flow through the portal vein,
which carries blood from the intestine and spleen to the liver.

The following is the text of a media advisory from Wiley-Blackwell, publisher of Hepatology, describing the study and it's findings.

Antiviral Therapy Impacts Esophageal Varices in HCV-Induced Cirrhosis

Study Shows Sustained Virologic Response Prevents EV

Italian researchers have discovered that antiviral treatment and sustained virologic response (SVR) prevents esophageal varices in patients with compensated hepatitis C (HCV)-induced cirrhosis, indicating that endoscopic surveillance can be safely delayed or avoided in these patients. Full findings are published in the June issue of Hepatology, a journal of the American Association for the Study of Liver Diseases (AASLD).

According to the National Digestive Diseases Information Clearinghouse (NDDIC), an estimated 4.1 million Americans have antibody to HCV (anti-HCV), indicating ongoing or previous infection with the virus. Researchers estimate that at least 20% of patients with chronic HCV develop cirrhosis. Progression of cirrhosis leads to portal hypertension, which can result in esophageal varices (EV) and other complications.

EVs are abnormally enlarged veins in the esophagus that occur when portal hypertension obstructs normal blood flow to the liver, causing blood to back up into the esophageal vessels. Esophageal varices can rupture which can be life-threatening. The onset of EV marks a crucial turning point in the outcome of cirrhosis. The research team led by Savino Burno, MD, set out to determine whether antiviral treatment resulting in SVR could prevent this condition.

The study, spanning from January 1989 to December 1992, evaluated 218 patients less than 70 years of age with compensated Child-Pugh class A cirrhosis who presented at three referral centers in Milan and tested positive for serum anti-HCV. Only subjects who agreed to undergo upper endoscopy at the time of enrolment and who were found to be EV-free were included. All 218 subjects had regular follow up with surveillance ultrasound for hepatocellular carcinoma (HCC) every six months and endoscopy every three years to identify de novo varices.

The standard antiviral regimens of recombinant alpha IFN monotherapy or combination with both IFN and ribavirin were administered, regardless HCV genotype, for at least six months and for an additional six-month period in patients who achieved a complete biochemical response. Combination therapy with IFN or pegylated IFN and ribavirin was administered in agreement with guidelines. SVR was defined as undetectable serum HCV RNA (< 50 IU/mL) six months after stopping therapy.

The primary endpoints were development of de novo varies or HCC. Of the 218 patients, 149 (68%) received HCV therapy and 34 (23%) achieved SVR and no EVs. During the follow-up of median 11.4 years, de novo EVs were detected equally among untreated and treated patients who did not achieve SVR. Sixty-seven patients, 7 of whom achieved SVR, developed HCC.

"Our study provides an accurate estimate of the 10-year cumulative incidence of EV in this population of patients," stated Dr. Bruno. "A major finding of our study, of great importance in clinical practice, is that the achievement of SVR abolishes the development of EV in the long-term. The reliability of our result is guaranteed by the ample length of observation among this group of patients. In routine clinical practice, serial surveillance by EGD can be safely delayed or avoided in SVR patients, sparing a significant amount of useless invasive and costly procedures."

The Milan study is the largest study with the longest follow-up to date that addresses the impact of SVR on the development of esophageal varices. In his editorial also published in Hepatology this month, Dr. Richard Sterling concurs, "If these results are confirmed, it may not be necessary to subject patients with HCV-induced cirrhosis to the expense and risks of repeated endoscopies." He further points out that the current study is the first to demonstrate a pharmacologic treatment to reduce (or in this case, eliminate) the development of varices. However, Dr. Sterling cautions, "Before we get too excited, we must remember that current treatment to achieve SVR in those with cirrhosis is difficult and there are often increased side effects, more cytopenias, and lower response rates than those without cirrhosis. Therefore, given the cost, both in dollars and resources, the increased side effects, and decreased response rates of HCV therapy, it remains to be determined if the "bang is worth the buck" in this select group of patients."

Investigator affiliations: Department of Internal Medicine, A.O. Fatebenefratelli e Oftalmico, Milan, Italy; Department of Internal Medicine, A.O. S. Paolo, Italy; A.O. Sondrio, Italy; Endoscopy Unit, A.O. S. Gerardo, Monza, Italy; Gastroenterology and Gastrointestinal Endoscopy Unit, Ospedale Policlinico, Milan, Italy; Department of Medical Sciences, University of Milan, Milan, Italy; Gastroenterology and Hepatology Unit, University of Palermo, Palermo, Italy; Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.

7/6/10

References

S Bruno, A Crosignani, C Facciotto, and others. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study. Hepatology 51(6): 2069-2076 (Abstract). June 2010.

RK Sterling. Long-term effects of sustained virologic response on the development of esophageal varices in compensated cirrhosis: "is the bang worth the buck?" Hepatology 51(6): 1891-1893. June 2010.

Other Source
Wiley-Blackwell. Antiviral Therapy Impacts Esophageal Varices in HCV-Induced Cirrhosis. Press release. May 25, 2010.

Source

Chronic Hepatitis C Linked to Increased Risk of Kidney Cancer


SUMMARY: People with chronic hepatitis C virus (HCV) infection have double the risk of developing renal cell carcinoma, or kidney cancer, according to a study published in the April 2010 issue of Cancer Epidemiology, Biomarkers and Prevention. While the reason for this link remains unclear, the researchers recommended that clinicians should carefully monitor and follow up on signs of kidney problems in hepatitis C patients, and people newly diagnosed with kidney cancer should be tested for HCV.

By Liz Highleyman

Chronic hepatitis C is primarily a disease of the liver, but it can also contribute to problems elsewhere in the body. HCV infection has been linked to kidney disease in the past. Stuart Gordon from Henry Ford Hospital and Wayne State University School of Medicine and colleagues aimed to determined whether this was true specifically for renal cell carcinoma (RCC).

The investigators analyzed data from the large racially/ethnically diverse Henry Ford healthcare system in Detroit The study cohort included 67,063 participants who were tested for HCV between 1997 and 2006, and followed to monitor development of RCC until April 2008; about 5% were HCV positive. The researchers used the health system's cancer registry to identify patients diagnosed with kidney cancer.

Results
  • 0.6% of HCV positive patients (17 out of 3057) developed renal cell carcinoma during follow-up, compared with 0.3% of HCV negative participants (177 out of 64,006).
  • The RCC cases in HCV positive patients included 8 clear cell cancers, 6 papillary cancers, 2 mixed clear cell/papillary, and 1 undifferentiated.
  • Among participants diagnosed with RCC, HCV positive patients were of a significantly younger average age than HCV negative patients (54 vs 63 years; P < 0.001).
  • In a univariate analysis, the hazard ratio for developing RCC among HCV positive patients was 2.20.
  • In a multivariate analysis that adjusted for other known kidney cancer risk factors including older age, male sex, black race, and chronic kidney disease, the hazard ratio for hepatitis C patients was 1.77, or a 77% increase in risk.
  • Men were 2.4 more likely to develop RCC than women.
  • African-Americans had about a 40% higher risk of developing RCC than other racial/ethnic groups.
  • Each additional year of age increased kidney cancer risk by about 3%.
  • Based on these findings, the study authors concluded, "Chronic HCV infection confers a risk for the development of RCC."
"The results of this study would suggest a more careful surveillance of newly diagnosed RCCs for the presence of HCV infection," they advised. "It is premature to recommend more comprehensive screening of HCV positive patients for this relatively uncommon neoplasm. However, a heightened awareness of an increased kidney cancer risk should dictate more careful follow-up of incidental renal defects when detected on imaging procedures in patients with chronic hepatitis C."

"These results add to growing literature that shows that the hepatitis C virus causes disease that extends beyond the liver, and in fact most of our HCV-infected kidney cancer patients had only minimal liver damage," Dr. Gordon said in a press release issued by Henry Ford Hospital.

Investigator affiliations: Division of Gastroenterology and Hepatology, and Departments of Urology and Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, MI; Wayne State University School of Medicine, Detroit, MI.

7/6/10

Reference
SC Gordon, D Moonka, KA Brown, and others. Risk for renal cell carcinoma in chronic hepatitis C infection. Cancer Epidemiology, Biomarkers and Prevention 19(4): 1066-1073 (Abstract). April 2010.

Other Source
Henry Ford Health System. Hepatitis C Infection Doubles Risk for Kidney Cancer. Press release. April 6, 2010.

Source

Aethlon Medical Announces Exosome Detection Assay

 Aethlon Hemopurifier.
(PRNewsFoto/Aethlon Medical, Inc.)

- Assay to distinguish exosomes by their specific chemical structures -

SAN DIEGO, July 7 /PRNewswire-FirstCall/ -- Aethlon Medical, Inc. (OTC Bulletin Board: AEMD), the pioneer in developing therapeutic filtration devices to address infectious disease and cancer, announced today that it has filed a provisional patent on behalf of its wholly owned subsidiary Exosome Sciences, Inc. (ESI), relating to the development of an assay that will allow researchers to detect exosomes in blood and other fluids.

Beyond the potential therapeutic benefits of eliminating immunosuppressive exosomes from circulation, researchers recognize that exosomes represent an important diagnostic target to determine progression and prognosis of both cancers and infectious disease conditions. However, the availability of functional assays that specifically detect exosomes is limited. At present, exosomes are generally characterized and purified by size chromatography and general protein assay, not by chemical structures specific to the exosome. The company's Enzyme Linked Lectin Specific Assay (ELLSA) is analogous to the well established enzyme linked immunosorbent assay (ELISA), and has been designed to bind specifically to carbohydrate structures common to exosomes, but not to healthy human cellular components. Each ELLSA plate allows for up to 96 exosome detection tests. Further analysis of the captured exosomes is possible through detection molecules such as antibodies linked to a specific biomarker on the exosome. "Our proprietary assay provides the potential for a previously unrecognized revenue stream and further augments the relationships we have established with thought leaders from the oncology field," stated Aethlon Chairman and CEO, Jim Joyce.

About Aethlon Medical

At Aethlon Medical, we create revolutionary devices to address infectious disease and cancer. Our devices are designed to be novel platform solutions that fill therapeutic voids or aid in disease diagnosis and monitoring.

Our Hemopurifier® is the first medical device to selectively target the removal of infectious viruses and immunosuppressive proteins from the entire circulatory system. We recently discovered that our Hemopurifier® captures tumor-secreted exosomes that suppress the immune system of those afflicted with cancer. Prior to this discovery, a therapeutic strategy to directly inhibit or reverse the immunosuppressive destruction caused by exosomes did not exist in cancer care. By eliminating this mechanism, we believe our Hemopurifier® can fill an unmet clinical need and provide the benefit of an immune-based therapy without adding drug toxicity or interaction risks to established and emerging treatment strategies.

Human studies have documented the ability of our Hemopurifier® to safely reduce viral load in both Hepatitis-C virus (HCV) and Human Immunodeficiency Virus (HIV) infected patients without the administration of antiviral drugs. However, our initial clinical and commercialization focus is to establish our Hemopurifier® as an adjunct therapy to enhance the benefit of both infectious disease and cancer treatment regimens. In this regard, we plan to commercialize our Hemopurifier® in India as we advance our clinical strategies in the United States and the European Union. In vitro studies conducted by government and non-government research institutes have also verified that our Hemopurifier® has broad-spectrum capabilities against bioterror and emerging pandemic threats. These studies have confirmed the capture of Dengue Hemorrhagic Virus, Ebola Hemorrhagic Virus, Lassa Hemorrhagic Virus, West Nile Virus, H5N1 Avian Influenza Virus, 2009 H1N1 Influenza Virus, the reconstructed Spanish Flu of 1918 Virus, and Monkeypox Virus, which serves as a model for human Smallpox infection.

As a therapeutic device, the Hemopurifier® provides us with a pipeline into four significant market opportunities:

1.Cancer: A treatment candidate to improve patient responsiveness to established cancer therapies by removing immunosuppressive exosomes from circulation.

2.Hepatitis-C Virus (HCV): As an adjunct therapy to accelerate viral load reduction at the outset of standard of care drug regimens.

3.Human Immunodeficiency Virus (HIV): Provides a potential therapeutic option for HIV-infected individuals to manage disease progression once they become resistant to antiviral drug regimens.

4.Bioterror and Pandemic Threats: Represents the most advanced broad-spectrum strategy to address untreatable bioterror and emerging pandemic threats.

The Hemopurifier® is an expansive multi-patented platform technology whose mechanism of action can be leveraged to provide therapeutic, diagnostic, and biomarker discovery solutions. As a therapeutic, the Hemopurifier® is a single-use disposable cartridge designed for implementation within the established infrastructure of dialysis machines and other blood circulatory pumps already located in hospitals and clinics worldwide.

In design, our Hemopurifier® is a selective filtration device containing affinity agents that tightly bind to high-mannose structures unique to the surface of exosomes produced by cancer and glycoproteins residing on the envelope of viruses. These agents are immobilized around approximately 2800 porous hollow fibers that run the interior length of our device. The resulting design provides us the novel ability to separate both exosome and viral targets away from blood cells so they can then be selectively and permanently removed from the circulatory system. In application, blood circulation is established into the Hemopurifier® via a catheter or other blood access device. Once blood flow has been established, treatment benefit is immediate as the entire circulatory system can pass through the Hemopurifier® in as little as 15 minutes.

Our wholly owned subsidiary, Exosome Sciences, Inc. (ESI) is focused on the development of exosome-targeted products and services that improve cancer diagnosis, provide post-treatment cancer surveillance, and aid in the discovery of biomarkers that allow doctors to optimize patient therapy. Additional information regarding Aethlon Medical and Exosome Sciences can be accessed online at http://www.aethlonmedical.com/.

Certain of the statements herein may be forward-looking and involve risks and uncertainties. Such forward-looking statements involve assumptions, known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements of Aethlon Medical, Inc. to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. Such potential risks and uncertainties include, without limitation, the capability of the Hemopurifier® to reduce viral loads and other disease conditions or to identify or treat disease conditions such as cancer, including the ability to capture exosomes and the impact that potential ability may have on disease conditions, the Company's ability to raise capital when needed, the Company's ability to complete the development of its planned products, the ability of the Company to obtain FDA and other regulatory approvals permitting the sale of its products, the Company's ability to manufacture its products either internally or through outside companies and provide its services, the impact of government regulations, patent protection on the Company's proprietary technology, product liability exposure, uncertainty of market acceptance, competition, technological change, and other risk factors. In such instances, actual results could differ materially as a result of a variety of factors, including the risks associated with the effect of changing economic conditions and other risk factors detailed in the Company's Securities and Exchange Commission filings.

Contacts:

James A. Joyce
Chairman, CEO
858.459.7800 x301
jj@aethlonmedical.com

John P. Salvador
Director, Communications & Investor Relations
858.459.7800 x307
jps@aethlonmedical.com

Jon Cunningham
RedChip Companies, Inc.
800.733.2447 x107
jon@redchip.com

SOURCE Aethlon Medical, Inc.

RELATED LINKS
http://www.aethlonmedical.com/

Source

Ringwood charity's warning over liver donor shortage

3:00pm Wednesday 7th July 2010

By Joanna Codd

A RINGWOOD-based national charity has issued a warning after the number of people seeking liver transplants rose by 17 per cent in a single year.

In National Transplant Week, the British Liver Trust is expressing concern that soaring rates of liver disease – most of which is preventable – mean there will not be enough donors to meet demand.

Currently 370 patients are registered as needing a liver transplant. Two people die each week while they wait for an organ to become available.

Alison Rogers, chief executive of the trust, warned: “This figure is set to increase further unless we see the upward mortality trend of liver disease fall.

“With only 100 extra liver transplants available in five years and more people being affected by liver disease each year, we are very concerned.

“Increasing rates of liver disease are not just driving demand for transplants; they are driving demand for all liver services and pushing up NHS costs.”

Of particular concern is non-alcoholic fatty liver disease, closely linked to obesity, which has increased by 360 per cent in the last two years.

Alcoholic cirrhosis, the leading cause of liver disease, has increased by a fifth in the last five years and led to 130 transplants last year alone.

Since 2006, there has also been at least a 10 per cent rise in liver transplants for causes such as hepatitis C, liver cancer, hepatic artery thrombosis and polycystic disease.

Liver disease is the only one of the five biggest causes of death to show a steady increase, killing more than 16,000 people in 2008. If trends continue, deaths from liver disease will double in 20 years.

The trust is calling for better treatment services and diagnosis rates; minimum alcohol unit prices; better awareness and recognition of fatty liver; testing for viral hepatitis and universal vaccination against hepatitis B.

Source
By GENE MARCIAL

Posted 7:30 AM 07/07/10

Company News, Columns, Investing, Health Care, Pfizer, Bristol-Myers Squibb, Merck, GlaxoSmithKline, Novartis, Abbott

It seems like the growing ranks of emerging biotechnology companies are always behind the eight ball in building up their financial resources to fund extensive research and clinical studies for novel therapies. The fountain of innovative drugs for Big Pharma, biotechs usually seek the help of financiers, venture capitalists and the like. But biotechs that are well on the road to advanced development of drugs resort to another funding strategy: Striking partnerships with large drugmakers.

One such company is Achillion Pharmaceuticals (ACHN), which had raised some $27 million last year but now needs a partner to advance development of its three products. One of them is a possible next-generation drug to fight chronic hepatitis C virus, an inflammation of the liver that has infected some170 million people worldwide.

"A Partnership or Two"?

"We are in the midst of doing several [Phase 2 clinical trials] for our products, so we have been in advanced talks with several of the major global pharmaceutical companies for almost a year now to forge one or two partnerships," says Michael D. Kishbauch, Achillion's president and CEO. He expects that sooner rather than later "we will sign a partnership or two" to fund the clinical studies and complete development of its hepatitis programs, a potentially multibillion market.

Major pharmaceuticals that are involved in or plan to participate in developing new treatments for hepatitis include Pfizer (PFE), Merck (MRK), Bristol Myers-Squibb (BMY), GlaxoSmith, (GSK) Novartis (NVS), Roche (RHHBY) and Abbott Laboratories (ABT). Kishbauch declines to identify which of the companies he's in discussions with because "our negotiations are in a very advanced and delicate stage right now."

Several of the drugmakers want to partner with Achillion on all three of its products. Those are ACH-1625, a potential next-generation treatment for chronic hepatitis C virus that some analysts expects will be the "best-in-class" treatment; ACH-1095, an "NS4A antagonist" also for fighting the hepatitis virus; and ACHN-2684, a molecule that targets NS3 protease found to be effective against a broad range of natural hepatitis variants.

However, Kishbauch says he would prefer having different partners for each of the drugs to make sure they all get all the attention and support they require. He's negotiating for a guarantee that the partners will advance the products to a level equal to standard-of-care products.

Once-a-Day Dosing

Some analysts believe Achillion's hepatitis drugs would be superior to products now in the market, such as interferon and Vertex Pharmaceutical's (VRTX) Telaprevir, which is being marketed by Johnson & Johnson (JNJ). The demonstrated potency and safety of Achillon's ACH-1625 looks very good," says Jason Kolbert, analyst at National Securities, who rates Achillion's stock, now at $2.20 a share, a buy. It's down from its 52-week high of $3.89 reached on Dec. 16, 2009. "I believe the best is ahead for Achillion because of its strong hepatitis program," says Kolbert.

In the recent IB clinical trials on ACH-1625, safety and tolerability in patients continued to be excellent, notes Kolbert. And the trials also showed "meaningful reductions in the key pharma paradigm for antiviral therapy," he adds. Telaprevir requires twice-a-day dosing, he notes, while ACH-1625 needs only once-daily dosing.

Kolbert says when the Phase 2 clinical trials for ACH-1625 get under way -- and when clinical studies for the two other drugs start next year -- "Achillion's stock will see a sharp rise in valuation."

Edward Nash, senior analyst at Roth Capital Markets, says with the data he has seen on ACH-1625, the drug has a "strong chance of being as potent as, if not more than, Telaprevir." Importantly, he adds, the dosing schedule and better side-effect profile make Achillion a "very attractive partner candidate for the big pharmaceuticals."

Multibillion-Dollar Market

Achillion's clinical performance with ACH-1625, says Nash, should attract investors looking to be involved in the important fight against hepatitis C virus. He rates the stock a buy with a 12-month price target of $12. If that price objective looks mighty high, it isn't when you consider the multibillion dollar hepatitis market and the probability that Achillion will find a partner or two to move its potential winners to market.

The three largest institutional investors in Achillion are Janus Capital Management, which owns a 12.95% stake; Clarus Ventures, with 11.39%; and Wellington Management with 6.12%. Janus and Wellington bought more shares, and none sold stock as of Mar. 31, 2010.

Tagged: biotech, biotech stocks, biotechnology, biotechnology stocks, drugmakers, hepatitis, hepatitis c, pharma, pharmaceutical stocks, pharmaceuticals

See full article from DailyFinance: http://srph.it/dAEzZq

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Why We Do Things That Aren't in Our Best Interests

Dan Ariely
Professor of Behavioral Economics, Duke University

We don't weigh the costs and benefits when we're tempted to text while driving.

July 7, 2010

Question: Why do we do things, like smoking and overeating, that aren't in our best interests?

Dan Ariely: There’s lots of... lot of behaviors like this. So the basic essence is the trade-off between the short term and the long term.

Let me give you kind of a personal story about this. When I was in hospital a long time ago I got a liver disease from a bad blood transfusion, and for a long time they didn’t know what it was and from time to time I would get some liver infection, it was kind of bad. And about seven years after I got injured, I was already out of the hospital, I was in grad school, I had another flare up, I had to check myself into hospital and they found out it was hepatitis C. And there was an experimental treatment at that time called interferon, said, “Why don’t you try this?” I was very happy to try it, because, you know, who would want to die from liver cirrhosis? And I basically got these injections, I had to inject myself three times a week for a year and a half. And these injections basically symbolized for me the kind of the essence of the human condition. Here was an injection that could potentially be very useful for me 30 years later, but what happened is that it also had very bad side effects. So every time I would take an injection, I would be sick for about 16 hours. Vomiting, shaking, fever, nothing really terrible compared to liver cirrhosis, but for sure unpleasant and now. And here’s the question: liver, really important; injection, slightly important, but now and for certain.

And that’s basically a trade-off we have everything. It’s about saving: not for good for now; good for the future. Exercising: not good for now; good for the future. Dieting, not good for now, good for the future. Safe sex: not so good for now; good for the future. Lots of things have these trade-off and in turns out that when you face these trade-offs, we often do what’s called a present bias focus. We focus on the present too much and as a consequence, we undermine the long term, the long-term effect. This is the problem of Adam and Eve, when you could ask yourself, you know, who would ever give up eternity in the Garden of Eden for an apple? Well, if you ever texted and drive at the same time, you basically have done this mistake, right? And most people have texted while driving.

And why do we do it? It’s not because we weigh the cost benefit analysis and we say it’s a really good idea to text while driving. It’s because we’re tempted at the moment to do something that we realize is really stupid from the long-term perspective.

Now, back to my story. When I, after a year and a half, there were two pieces of good news, the first one was that my liver was working fine and there was no trace of the disease. The second thing that the doctors told me was that I was the only patient they ever had who took the medication on time. The question is, how could I do it? Do I have nerves of steel, am I not succumb to temptation? And the answer is, of course: we all succumb to temptation all the time, there’s no difference. But what I did was I found a trick. And my trick is that I love movies, if I had time, I would watch lots and lots of movies. So every Monday, Wednesday, and Friday on the way to school, I would stop at a video store, I would rent two or three videos I really wanted to see, I would carry them in my backpack the whole day, anticipating watching them. I would get home, I would give myself the injection, I would push a video in. I would get the bucket, I would get the blanket, I was already to the side effect, and I would start the video immediately. I wouldn’t wait for the side effect to settle in, I started immediately.

Now, you can ask yourself, did I really care about my liver and the answer is no. The fact is, that the liver is really important and me and all the other patients should have kept on taking our medication on time because of the liver, but it wasn’t strong enough. So what did I do? I substituted the liver with movies. Now, you might say, this is a stupid idea! Liver is really important, movie is not that crucial. If you ask me what do I prefer, movies or liver, you know, there’s no question. But because the liver is in the future, it was vastly discounted and because the movies were in the immediately, it was actually motivating me. And we call this "reward substitution." When I behave as if I care about my liver, by actually caring about movies.

And I think there’s actually a big lesson there. You can think about how do we get people to care about their health and money and longevity and so on, can we really get people to wake up every day and care about those things that will happen 30 years from now? The answer is, it will be very difficult, expensive, and unlikely, but can we find other reward substitutions. Can we get people to behave because of other things in a way that would make them behave as if they care about the thing that they’re doing for.

So why do people go to the gym, right? Do they really wake up every morning worrying about how they will look... feel like 30 years from now? Probably not, but can we get them to do something that is about the moment, to actually get them to behave because they do something that makes them care about, behave as if they care about something else. And I think that reward substitution actually provides a general answer to lots of problems in human behavior, we just need to find out what these rewards can be.

Question: Are there adaptive reasons that humans do things which aren't in our self-interests?

Dan Ariely: Absolutely! So if you think about the question of trust and revenge, that’s a great example. The fact is that we live in a society, we’re inherently social animals, unlike some other species and because of that, we need things that kind of connects us in a social way. So we have this social utility in which we just care about other people. Now, that creates lots of problems. For example, if you do a favor to me, I’ll like you more, and then it might put me in conflict of interest because I would want to reciprocate in some way, or, you know, trust and revenge and all of those things.

So, the fact is that there are some things that we are irrational and we would’ve liked to fix it, but there are some things where our irrationality is actually what allows us to live in a society. And if we lived as individual organisms that basically had no social ties and we’re just working each one of us separately, it will be a very different social structure. But we might want to actually have different strategies for our decision making, but because we’re inherently social animals, there’s all kinds of things that are irrational from the perspective of thinking that everybody’s a social, is a selfish maximizer, but nevertheless makes sense when you think about people as social animals.

The other thing, of course, is about processing information. So the fact is that we have a limited brain, you know, we’re kind of limited physically in many ways, right? We can’t jump very high, we can’t sustain cold or heat, I mean, think about all the stuff in the world that we do to make ourself more comfortable. We have chairs and clothes and glasses and headphones. I mean, lots and lots of stuff. It turns out our brain is also not perfect, right? In the same way that our bodies are not perfect, we can’t do everything we would like to, we’re not superman, our brain is also not perfect. Our brain processes information in a certain way and the reality that we experience is not out there, it’s in here. That’s what gives us, the brain gives us the world. Brought to us courtesy of our brain and its processing ability. And because the brain is not perfect, the way we get information and process it is also not perfect. And that’s just kind of functional, structural limitations to how rational we can be. And the fact is that we better recognize it, it’s really good to recognize it and the standard limitations and act accordingly. If we don’t, you know, we’ll just make more and more mistakes. We’ll just assume that we can be perfect, we’ll create a world as if people can be perfect and then we’ll just set us up to disappointment time after time.

Recorded on June 1, 2010

Interviewed by David Hirschman
 
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