November 14, 2010

Gastroenterology. 2010 Nov 3. [Epub ahead of print]

Shimakami T, Welsch C, Yamane D, McGivern D, Yi M, Zeuzem S, Lemon SM.

Division of Infectious Diseases, Department of Medicine, Inflammatory Diseases Institute, and the Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Abstract

BACKGROUND & AIMS: Several small molecule inhibitors of the hepatitis C virus (HCV) NS3/4A protease have advanced successfully to clinical trials. However, the selection of drug-resistant mutants is a significant issue with protease inhibitors (PIs). A variety of amino acid substitutions in the protease domain of NS3 can lead to PI resistance. Many of these significantly impair the replication fitness of HCV RNA replicons. However, it is not known whether these mutations also adversely affect infectious virus assembly and release, processes in which NS3 also participates.

METHODS: We studied the impact of 25 previously identified PI-resistance mutations on the capacity of genotype 1a H77S RNA to replicate in cell culture and produce infectious virus.

RESULTS: Most PI-resistance mutations resulted in moderate loss of replication competence, although several (V36A/L/M, R109K, and D168E) demonstrated fitness comparable to wild type, whereas others (S138T and A156V) were severely impaired both in RNA replication and infectious virus production. Although reductions in RNA replication capacity correlated well with decreased yields of infectious virus for most mutations, a subset of mutants (Q41R, F43S, R155T, A156S, and I170A/T) reproducibly demonstrated greater impairment in their ability to produce virus than predicted from reductions in RNA replication capacity. More detailed examination of the I170A mutant demonstrated no defect in release of virus from cells, and no significant difference in specific infectivity of extracellular virus particles.

CONCLUSIONS: Replicon-based assays might underestimate the loss of fitness caused by PI-resistance mutations, as some mutations in the NS3 protease domain specifically impair late steps in the viral lifecycle that involve intracellular assembly of infectious virus. All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.

Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

PMID: 21056040 [PubMed - as supplied by publisher]

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Am J Gastroenterol. 2010 Nov 9. [Epub ahead of print]

Kramer JR, Kanwal F, Richardson P, Giordano TP, Petersen LA, El-Serag HB.

[1] Houston VA Health Services Research & Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA [2] Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.

Abstract

OBJECTIVES: Several patient characteristics are known to impact hepatitis C virus (HCV) antiviral treatment rates. However, it is unclear whether, and to what extent, health-care providers or facility characteristics impact HCV treatment rates.

METHODS: Using national data obtained from the Department of Veterans Affairs (VA) HCV Clinical Case Registry, we conducted a retrospective cohort study of patients with active HCV viremia, who were diagnosed between 2003 and 2004. We evaluated patient-, provider-, and facility-level predictors of receipt of HCV treatment with hierarchical logistic regression.

RESULTS: The overall HCV treatment rate in 29,695 patients was 14.2%. The strongest independent predictor for receipt of treatment was consultation with an HCV specialist (odds ratio=9.34; 8.03-10.87). Patients were less likely to receive HCV treatment if they were Black, older, male, current users of alcohol or drugs, had HCV genotype 1 or 4, had higher creatinine levels, or had severe anxiety/post-traumatic stress disorder or depression. Patients with high hemoglobin levels, cirrhosis, and persistently high liver enzyme levels were more likely to receive treatment. Patient, provider, and facility factors explained 15, 4, and 4%, respectively, of the variation in treatment rates.

CONCLUSIONS: Treatment rates for HCV are low in the VA. In addition to several important patient-level characteristics, a specialist consultant has a vital role in determining whether a patient should receive HCV treatment. These findings support the development of patient-level interventions targeted at identifying and managing comorbidities and contraindications and fostering greater involvement of specialists in the care of HCV.Am J Gastroenterol advance online publication, 9 November 2010; doi:10.1038/ajg.2010.430.

PMID: 21063393 [PubMed - as supplied by publisher]

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Am J Gastroenterol. 2010 Nov 9. [Epub ahead of print]

Reau N, Satoskar R, Te H, Devoss A, Elsen C, Reddy G, Mohanty S, Jensen D.

University of Chicago Medical Center, Center for Liver Disease, Chicago, Illinois, USA.

Abstract

OBJECTIVES: Early viral kinetics accurately predicts sustained virological response (SVR) in genotype 1 patients with hepatitis C virus (HCV) undergoing therapy with pegylated interferon (PEG) and ribavirin (RBV). No baseline factor has a stronger predictive role. Early identification of patients unlikely to respond is equally important, allowing early treatment modification or discontinuation. The aim of this study was to determine whether 4-week null response (eNR) correlates directly with 12-week null response and inversely with SVR.

METHODS: A retrospective analysis of HCV patients treated at our institution was done. Patients were classified based on a 4-week viral log decline compared with baseline: <1 log, ≥1 log, <2 log, ≥2 log, <3 log, ≥3 log without rapid virological response (RVR) and with RVR. eNR was defined as less than a 1 log change from baseline.

RESULTS: A total of 159 patients had quantitative HCV-RNA PCR at treatment week 4, of whom 24% (38) experienced eNR. In all, 22 (58%) of the eNR patients were African American, 58% male, 32% cirrhotic, average age 53 years (range 36-71), 89% (33) genotype 1, and average baseline viral load was 5.9261 log (range 3.1492-7.3025). On-treatment response demonstrated failure to attain early virological response (EVR; 2-log decline at week 12) in 50% (19) and partial EVR (pEVR) in 39% (15). Three (8%) patients with eNR achieved SVR. In our patient population, eNR had 92% negative predictive value (confidence interval 83.5-100%) for SVR and was the strongest single predictor for treatment failure, including the baseline factors genotype and viral load.

CONCLUSIONS: eNR is strongly associated with null response or pEVR and accurately predicts failure to attain SVR. Consideration should be made to discontinue or modify therapy in patients with eNR who receive the appropriate weight-based PEG/RBV.Am J Gastroenterol advance online publication, 9 November 2010; doi:10.1038/ajg.2010.424.

PMID: 21063395 [PubMed - as supplied by publisher]

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AASLD: Genotype 1b vs 1a and Peg/Rbv Lead-In

by Jules Levin, NATAP

The phase 3 presentations at the recent AASLD did not address the genotype 1a vs 1b question, difference in SVR rates but here is data from phase 2. In studies at AASLD and other previous studies examining oral HCV drug regimens that did not contain peg/rbv genotype 1a often is associated with the development of more drug resistance and higher viral failure rates. A more potent regimen and the use of a nucleoside or nucleotide in the regimen would be expected to help, but what's the affect of adding peg/rbv to 1 oral, either boceprevir or telaprevir. Phase 3 presentations of both drugs at AASLD did not address this but here is what I found from phase 2 data.

from Lancet Aug 2010 SPRINT1 publication:

Efficacy of boceprevir, an NS3 protease inhibitor, in combination ...
Aug 9, 2010 ... The aim of the hepatitis C virus SPRINT-1 (Serine Protease Inhibitor Therapy-1) study was to establish the safety and efficacy of boceprevir ...
www.natap.org/2010/HCV/080910_01.htm

In the boceprevir groups, the lead-in groups were associated with a modestly lower rate of breakthrough than were the groups with no lead in. Combining across treatment groups, the rate of breakthrough in the boceprevir lead-in groups was 4% (nine of 206) compared with 9% (19/210) in the boceprevir groups with no lead in (p=0·057).

The lead-in (PR4) allowed us to examine the relation of peginterferon and ribavirin responsiveness at week 4 to SVR with boceprevir-containing regimens. In the PR4 28-week or 48-week groups, SVR was similar in participants with greater than 1·5 log10 reduction in hepatitis C virus RNA from baseline before the addition of boceprevir. Higher SVR was noted in participants who received PRB for 44 weeks with less than 1·5 log10 reduction from baseline at PR4 (figure 5). In patients with less than 1 log10 reduction with PR4, 55% (95% CI 32-76) SVR was noted in the PR4/PRB44 group.

The viral response during the lead-in could help to predict best possible treatment duration. Patients achieving less than 1·5 log10 reduction in viral level after PR4 benefit most from a treatment duration of 48 weeks, whereas those with greater than 1·5 log10 reduction show similar SVR irrespective of treatment duration of 28 weeks or 48 weeks.

The lead-in can identify null responders to peginterferon alfa-2b and ribavirin, who seem to be at greatest risk for treatment failure with specifically targeted therapies and for development of resistance. However, in our cohort, a substantial proportion of null responders during the lead-in period went on to achieve SVR with the addition of boceprevir.16, 27

This study assessed the use of a PR4 lead-in before the addition of boceprevir, as well as the effect of starting all three drugs concomitantly, and compared these groups with PR48 control. In the novel lead-in approach, we recorded increased SVR and a reduction in relapse and breakthrough, and allowed for potential determination of treatment duration on the basis of responsiveness to the PR4 lead-in. However, in the direct comparison between lead-in and non-lead-in groups, relapse reduction did not differ significantly, although the absence of a statistically conclusive result is not surprising since the sample size did not allow detection of modest diff erences between lead-in and non-lead-in groups.

Table 4: Factors aff ecting sustained virological relapse (genotype 1b predicts better respons ethan 1a, but clearly 1a responds.)


PR4 (lead-in)=peginterferon alfa-2b 1·5 µg/kg plus ribavirin 800-1400 mg per day for 4 weeks. PR48 (control)=peginterferon alfa-2b 1·5 µg/kg plus ribavirin 800-1400 mg per day for 48 weeks. PRB24/28/44/48=peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24, 28, 44, or 48 weeks. OR=odds ratio. SVR=sustained virological response. HCV=hepatitis C virus. *For each baseline subgroup, the odds ratio and 95% CI for treatment eff ect (PR4/PRB44 vs PR48) are based on logistic regression model with adjustment for stratification factors (race and cirrhosis status). Significant predictor of SVR based on multivariable logistic regression analysis (all boceprevir-containing groups combined): race (non-black vs black; OR 2·7, 95% CI 1·49-5·04); genotype (1b vs 1a/other; 2·0, 1·22-3·32); baseline viral load (low vs high; 2·3, 1·04-5·12); and standardised baseline platelet count (continuous; 0·8, 0·61-0·94). Viral genotype was measured with the TruGene assay (Bayer HealthCare, Berkeley, CA, USA). §Analyses of the relations between SVR and hepatitis C virus genotype, fasting glucose, and baseline platelet count were not preplanned. Baseline platelet count included in multivariable logistic regression analysis as a continuous variable, standardised by transforming each patient's count as: (count-overall mean)/(overall SD). SVR rates are provided as descriptive statistics for platelet count intervals based on mean and SD: 169·5=1 SD below mean; 237·4=mean; 305·4=1 SD above mean. Data are number (%) for pooled boceprevir groups.

Telaprevir PROVE 2 publication NEJM April 30 2009:
Independent Predictors of Sustained Virologic Response
The association between a sustained virologic re- sponse and independent variables was explored with the use of a logistic-regression model. Treat- ment group and baseline HCV RNA level were the only two variables significantly associated with a sustained virologic response (P<0.001) (Table 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).

PROVE1
The viral population at the time of breakthrough consisted predominantly of variants containing mutations V36M and R155K (in 10 patients infected with HCV genotype 1a) or A156T (in 1 patient with HCV genotype 1b). The remaining patient had missed several days of dosing and had a breakthrough at day 8; this patient was infected with predominantly wild-type virus.

In PROVE2 (genotype 1b was not a significant predictor but a nonsignificant predictor):
Supplementary Table 1. Independent predictors of an SVR in multivariate analysis of baseline parameters. The following baseline variables were included in the analysis: gender, age (less or more than 45 years), BMI, baseline HCV RNA level (less or more than 800,000 IU/mL), genotype 1 subtype (1a vs 1b), ALT level, glucose level and treatment arm. Variables with a weak association (P>0.20) with the SVR in the initial logistic regression model were excluded from the final model. 95% CI: 95% confidence interval.

A National Strategy for Viral Hepatitis Control: AASLD 2010

EXPERT VIDEO COMMENTARIES:
Robert G. Gish, MD
Posted: 11/12/2010
View video here

Video transcript:

Hello, I'm Robert Gish. I will be starting as Chief of Hepatology at the University of California, San Diego, in San Diego, California, on December 1, as well as being Medical Director, Center for Hepatobiliary Disease and Abdominal Transplantation.

I'm here at the AASLD [American Association for the Study of Liver Diseases] 2010 in Boston, and I'd like to comment on this year's President's Choice lecture[1] for Medscape. This lecture focused on the findings of the Institute of Medicine study, Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C.[2]

What are the findings and what are the clinical implications for hepatitis B and C?

Dr. Koh, during his presentation, talked about the new affordable care and portability insurance act that was put in place by our government. First, they wanted to raise awareness. It was emphasized that there are at least 5 million people who are infected with hepatitis B and C today. I think there are really 7 million people infected, and during his presentation, Dr. Koh at least hinted at that possibility. Very importantly, whatever the denominator is, we think at least two thirds of individuals do not know that they are infected at this time.

The goals are to attain the highest standard of health and to mobilize medical and community leadership to focus on hepatitis B and C. There is also a new Healthy People program that starts in December 2010, focusing on life, quantity, quality, equity, promotion of healthy behaviors, and also changing the environment to change the individual's and the community's health.

There are at least 3 major at-risk communities that need to be focused on with respect to viral hepatitis. These are the Asia-Pacific Islander community, those individuals with high-risk sexual behavior, and those with high-risk behavior in general who may have blood or needle exposure.

Another major point was to bring guidelines about viral hepatitis from many different organizations and make those consistent, so the community can get a consistent message about screening, surveillance, linkage to care, and vaccination, as well as behavior modification.

There was another major emphasis on developing multidisciplinary teams. We have a major workforce shortage. We need more liver specialists, more engagement from the infectious disease community for viral hepatitis B and C, and more primary care, and this includes nurses, nurse practitioners, and physician's assistants.

New screening efforts are going to be promoted by the Centers for Disease Control and Prevention (CDC). There was also an emphasis on current screening programs such as the San Francisco HBV [hepatitis B virus] free program that I've been involved with for more than 3 years. In San Francisco, we have screened nearly 8000 individuals and have found a prevalence rate in the 3% to 7% range for hepatitis B. New York City is replicating this program, and there's a move underway to actually have a US-wide HBV free program.

Now, the Trust for America's Health has also come into effect and is setting up a collaboration, not just with the AASLD, but across the CDC and many other leadership organizations, to help bring this Institute of Medicine program into full effect. Health and Human Services is putting together a task force with the Health Resource Services Administration, the Food and Drug Administration, and the CDC. Importantly, we need to educate providers to enhance screening and linkage to care and [we need] to decrease vaccine-preventable diseases by implementing a much higher and more effective vaccine policy. We want to decrease high-risk behavior and, of course, protect our healthcare worker colleagues.

Systems of care can be both amplified and enhanced. Federally qualified community health centers will probably double the number of individuals that they take care of, from 19 million to 40 million. Integrating programs that are already in place with HIV care and addiction medicine was also emphasized. We want to enhance vaccinate rates, and the emphasis on this across all these programs was brought forward. Networking with the American College of Physicians, the American Academy of Family Practitioners, and nurse practitioner organizations was also discussed.

In closing, many fantastic ideas and concepts were put forth during this lecture, but we need to confirm that financing will follow this important proposed structure.

Thank you for joining us. This is Robert Gish for Medscape.

Source

Also See:
AASLD President's Choice Lecture: The National Strategy for the Control of Viral Hepatitis and Liver Cancer

A New Era of Hepatitis C Therapy: AASLD 2010

EXPERT VIDEO COMMENTARIES:
Zobair M. Younossi, MD
Posted: 11/12/2010
View video here

Video transcript:

Hello, I'm Zobair Younossi, Executive Director of the Center for Liver Diseases and Vice President of Research at the Inova Health System in Falls Church, Virginia.

Today, I'm at the 2010 American Association for the Study of Liver Diseases (AASLD) meeting in Boston. We're going to discuss some of the new developments, both here and around this meeting, related to hepatitis C.

As you know, the current standard treatment for hepatitis C is to use a combination of pegylated interferon-alpha-2A or 2B and ribavirin. When you use this combination, you will achieve a 50% to 55% sustained virologic response (SVR) rate with sustained viral eradication. In fact, these rates are lower in patients who have genotype I and who receive a full year of treatment, with 40% to 45% of them achieving sustained virologic response.

However, in 2010, we're entering a new era in the treatment of hepatitis C. The recent developments in hepatitis C, including those discussed at this liver meeting, will bring us closer to the practice of personalized medicine for patients with chronic hepatitis C. There are 3 important areas of advancement: first, response-guided therapy for chronic hepatitis C treatment; second, biomarkers for predicting response to treatment of hepatitis C; and third, development of targeted therapy for hepatitis C.

Response-guided therapy. Response-guided therapy really uses HCV [hepatitis C virus] RNA testing during treatment to predict response and guide treatment for patients with chronic hepatitis C. This information can be summarized by documenting that the earlier the HCV RNA becomes negative for these patients during treatment, the higher the chance of achieving SVR or durable response. [In addition], those patients who achieve rapid virologic response, for example, by 4 weeks they are undetectable in terms of HCV RNA, they may need an even shorter course of treatment. In fact, these data seem to be applicable to newer regimens that are being developed for hepatitis C.

Predicting response. The next advance in hepatitis C is the development of biomarkers that are capable of predicting SVR in patients with hepatitis C who are scheduled to be treated with antiviral therapy. Recently, a new genomics biomarker called IL-28B was developed that predicts SVR in genotype I patients who are treated with pegylated interferon and ribavirin. Those patients with HCV genotype I whose IL-28B test shows that they have the "C-C allele" rather than the "T-T allele" will have a much higher chance of achieving SVR. In fact, 70% to 80% of them will achieve SVR vs approximately 20% to 25%. This allele may explain the great deal of heterogeneity that we have been seeing over the past few decades in the treatment of hepatitis C.

Targeted therapy. The third exciting area of advancement in hepatitis C is the development of targeted therapy. Specifically, we have seen data on the new direct-acting antivirus for hepatitis C, also called STAT-C [specifically targeted antiviral treatment for hepatitis C] treatment. These agents are new drugs that will target viral enzymes that are important for replication of hepatitis C and block these enzymes from allowing the hepatitis C virus to replicate.

There are 2 categories of direct antivirals, one category is called protease inhibitors, and the other one is polymerase inhibitors. Protease inhibitors that are furthest along in development are telaprevir and boceprevir. Telaprevir is an inhibitor of NS3/NS4 HCV serine protease. The best efficacy of this agent has been seen when it's used in triple combination regimen, combined with standard of care pegylated interferon and ribavirin, for the first 12 weeks followed by another 12 or 36 weeks of treatment.

Boceprevir is an NS3 serine protease inhibitor. It is most efficacious when it is used in triple combination, also with pegylated interferon and ribavirin. In fact, most of the studies require that this drug be used after a full week lead-in phase of combination standard treatment followed by 44 weeks of triple combination therapy.

When you're looking at the efficacy of these triple combination therapies, they are similar and they are significantly higher than what you see with double combination therapy for patients with genotype I. For patients who have never been treated before, or so-called "naive" patients, the sustained virologic response is somewhere between 70% and 75%. In fact, if you use response-guided therapy, as I mentioned earlier, the response rate is even higher, especially for telaprevir. SVR for nonresponders or treatment-experienced patients is as high as 65%. However, if you categorize patients in terms of whether they will relapse or are nonresponders, meaning they have never responded before, the response rate of these drugs in relapsers is 85% to 90%, and in those who are called nonresponders, about 30% to 35%.

One important difference between these 2 regimens is duration of the combination that is required. With telaprevir, 12 weeks of triple combination is required. With boceprevir, triple combination must be provided for the full course (44 weeks) of treatment.

Of course, by adding new drugs you'll see added side effects, which are anemia for both drugs and rash for telaprevir.

In summary, these exciting data suggest that we have already entered or will shortly enter the new and exciting area of personalized medicine in treatment of hepatitis C patients by using response-guided therapy, IL-28B biomarkers, and once approved, regimens that would include targeted therapy with triple regimens that include protease inhibitors.

Thank you again for joining us. This is Dr. Zobair Younossi for Medscape.

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What's New in Chronic Hepatitis B: AASLD 2010

EXPERT VIDEO COMMENTARIES:
Paul Martin, MD
Posted: 11/12/2010
View video here

Video Transcript:

Hello. I'm Paul Martin, Professor of Medicine, Chief of Hepatology at the University of Miami in Florida. I'm here at AASLD [American Association for the Study of Liver Diseases] 2010 in Boston [Massachusetts], and I'd like to review some of the sessions on hepatitis B for Medscape.

The first study that I wanted to discuss is what I call the inactive carrier state revisited. This is a study by Simons and colleagues from Alaska,[1] in which they studied 97 chronically infected Alaskan natives who had persistently normal alanine aminotransferase (ALT) levels with low-level hepatitis B virus (HBV) DNA levels. These individuals were followed over a period of several years.

In these 97 patients, they identified 3 patterns of activity. Some patients had a steady low-level replicative state. Other patients had fluctuating replication with a change in HBV DNA levels in a magnitude of 2-3 logs. Then, finally, a group of patients were persistently HBV DNA negative.

Very importantly, in each of these 3 groups, the ALT levels stayed normal, and these individuals would be normally characterized as in the inactive carrier state, but very importantly, the third group, who had an absence of HBV DNA during the period of follow-up, went on to lose hepatitis B surface antigen in a significant number of instances. Indeed, of the 97 patients in this study, 16 of whom have lost surface antigen, 14 of these came from the group with persistently negative HBV DNA.

The investigators have coined the term "elite control group," and this suggests that even with the apparently inactive carrier state, there are subsets of patients whose prognosis differs. It is crucial to determine for long-term follow-up whether there is a complete absence of HBV DNA, because this seems to predict a high likelihood of ultimate clearance of hepatitis B surface antigen.

The next study that I want to discuss is a study comparing tenofovir vs tenofovir and emtricitabine in adefovir-experienced patients. This was reported by Berg and colleagues.[2] The entry criteria for this particular study were adefovir use in patients who remained persistently HBV DNA negative, in this instance greater than 1000 copies/mL with ALT levels less than 10 times the upper limits of normal. Of importance, 58% of the group as a whole had previous lamivudine exposure.

In this long-term study, by week 156, 85% of the patients enrolled had excellent suppression of HBV DNA, down to less than 400 copies/mL. Very importantly, this included 10 adefovir-resistant patients, and as I mentioned earlier, more than half of the patients also had previous lamivudine exposure. Of importance, in this study, in terms of control of replication, there was no difference between tenofovir and a combination of tenofovir and emtricitabine. This suggests for patients who have had a suboptimal response to adefovir, the use of tenofovir over a protected period of time leads to excellent control of hepatitis B replication, including in this study a small group of patients who were adefovir resistant.

The final study that I want to discuss looks at long-term efficacy of tenofovir in patients who had a high baseline viral load. This was reported by Gordon and colleagues,[3] and the study included both HBeAg+ and HBeAg- patients. In this study, by the end of follow-up, 75% of the patients had achieved an HBV DNA less than 200 copies/mL, and 23% of the HBeAg+ patients had seroconverted, that is, had lost e antigen and had developed an e antibody. Very importantly, in the HBeAg+ patients overall, 15% of these individuals cleared the hepatitis B surface antigen. During this long-term study, no resistance was detected.

The important implications of this study include the fact that there is excellent control of even high-level replication in patients with chronic hepatitis B infection, and, ultimately, many of these individuals will go on to clear hepatitis B surface antigen. Finally, over a 4-year period, no resistance was observed. This confirms earlier studies that suggest there is a very low rate of intrinsic resistance with tenofovir therapy.

Thank you for joining us. This is Paul Martin for Medscape.

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New Sources of Liver Injury in Children: AASLD 2010

EXPERT VIDEO COMMENTARIES:
William F. Balistreri, MD
Posted: 11/10/2010
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Video Transcript:

Hello. I'm Dr. Bill Balistreri, Professor of Pediatrics at the University of Cincinnati College of Medicine and Cincinnati Children's Hospital. I'm here in Boston for the annual American Association for the Study of Liver Diseases (AASLD) Liver Meeting, and I'd like to review for Medscape some of the novel research related to pediatric liver disease.

Research presented this week offers new insight into what is the most vexing problem in pediatric hepatology: biliary atresia. This inflammatory fibro-obliterative disease of the bile ducts often leads to cirrhosis and, therefore, accounts for more than 50% of liver transplants done in children. The cause is not known, so this has been a very frustrating experience for those of us who must take care of these children. However, data presented here strongly suggest that bile duct injury in biliary atresia is due to a virus-induced autoreactive T-cell- mediated inflammatory insult. In several studies, animal models have shown that regulatory T-cell dysfunction and deficiency of hepatic CD4-positive cells appear to be important components of the cascade that leads to bile duct injury and, therefore, to the disease manifested as biliary atresia.

These observations certainly offer novel therapeutic approaches to this disease, as I mentioned, which is the most vexing problem that we must face. In a related clinical observation, results from a cross-sectional multicenter registry indicate that portal hypertension was present in 50% of 163 children with biliary atresia. This was manifested by variceal bleeding, ascites, hepatopulmonary syndrome, and/or splenomegaly. Compared with those children without portal hypertension, affected patients with biliary atresia had significant differences that could be measured. These were differences in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and bilirubin levels, and significantly lower white blood cell counts and platelet counts. It will be important to follow up this cohort of children. This will allow insight into the natural history of portal hypertension in biliary atresia and allow us to stage our therapeutic efforts.

Several studies here have focused on another cause of liver injury: drug-induced hepatotoxicity. While acute hepatotoxicity due to acetaminophen is well known, the impact of chronic, perhaps low-dose exposure to this drug, which is very widely used in children, is less well-appreciated. Data are emerging from a multicenter study that examined this issue. The biochemical profile of children with acute liver failure who had chronic exposure to acetaminophen was quite unique. It was characterized by lower bilirubin levels and higher peak ALT levels than patients with acute liver failure who did not have acetaminophen exposure. This gives us an important index by which to make an early diagnosis. In addition, the outcomes of these children were also worse than for those with single toxic exposure to acetaminophen. This observation should lead to enhanced recognition and hopefully to more effective preventive efforts to reduce exposure to this commonly used agent.

In another important observation, hepatitis E virus (HEV), which was previously thought to be uncommon in North America, is being increasingly recognized here as a cause of acute and perhaps chronic liver disease. At this meeting, a high prevalence of serologic evidence of HEV exposure was reported in children who had undergone liver transplantation. The investigators documented chronic inflammation, often leading to cirrhosis, which was presumably related to HEV infection occurring in an immune-compromised host. This report suggests that it may be time to screen for this agent, HEV, especially in high-risk children.

One final observation: as we all know, an emerging problem in children is fatty liver disease. This parallels the obesity epidemic. However, recognition of fatty liver disease and its consequences and certainly management of these children remains problematic. Studies presented here have documented that the combined use of 2 methods, the pediatric nonalcoholic fatty liver disease (NAFLD) fibrosis index and transient elastography (a measure of liver stiffness), can accurately detect the presence of significant fibrosis in children. These tools may offer a clinically useful noninvasive method to assess and monitor the progression to nonalcoholic steatohepatitis (NASH) in children with fatty liver disease.

In conclusion, the novel observations reported here this week will hopefully lead to transformation in our care of children with liver disease. I want to thank you for joining us. This is Dr. Bill Balistreri for Medscape.

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Rebetol (ribavirin) capsules and oral solution

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) – October 2010

Summary View

WARNINGS AND PRECAUTIONS
Concomitant administration of Azathioprine

Pancytopenia (marked decreases in red blood cells, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. PegIntron, Rebetol and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine.

Source
Journal of Viral Hepatitis
Volume 17, Issue 12, pages 879–886, December 2010

P. R. Spradling 1, J. T. Richardson 2, K. Buchacz 3, A. C. Moorman 3, J. T. Brooks 3, the HIV Outpatient Study (HOPS) Investigators †

1 Division of Viral Hepatitis, National Center for HIV, Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA
2 Cerner Corporation, Vienna, VA
3 Division of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA

* Correspondence: Philip R. Spradling, MD, Division of Viral Hepatitis, National Center for HIV, Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Mailstop G37, 1600 Clifton Road, N.E., Atlanta, GA, USA. E-mail: pspradling@cdc.gov

Article first published online: 11 FEB 2010
DOI: 10.1111/j.1365-2893.2009.01249.x
© 2010 Blackwell Publishing Ltd

Abstract

Keywords: coinfection; HBV;HIV; prevalence;testing

Summary.  Coinfection with hepatitis B virus (HBV) is an important and preventable cause of chronic liver disease among HIV-infected patients. We calculated the prevalence of chronic HBV infection annually from 1996 to 2007 by age, gender, race/ethnicity, and HIV transmission risk in a multisite observational cohort study of HIV-infected patients. Prevalence of chronic HBV infection was calculated as the number of patients with a positive HBsAg or detectable HBV DNA divided by the number of patients tested using either one of these assays. Among 4467 (59%) patients tested for chronic HBV infection from a total of 7618 patients active during 1996–2007, median age was 38.5 years, 77% were men, 49% were white, 35% were black, 13% were Hispanic, and 53% were men who had sex with men (MSM). Overall, 8.4% tested positive for HBsAg or detectable HBV DNA. Annual chronic HBV prevalence during 1996–2007 ranged from 7.8% to 8.6% without a statistically significant trend. Overall, prevalence was greater among men compared with women; among whites, blacks, and persons of other race compared with Hispanics; among MSM compared with injection drug users and high-risk heterosexuals; and among patients aged 35–44 years compared with younger or older patients. MSM constituted the greatest fraction (63–72%) of all HBV-infected patients in the HIV Outpatient Study (HOPS) over the period. Of eligible patients, 5.8%, 23.4%, and 31.6% had received at least one dose of HBV vaccine by years 1996, 2002, and 2007, respectively. Despite the availability of an effective HBV vaccine for over two decades and long-standing recommendations for immunization of persons (with or without HIV infection) at risk for HBV, the prevalence of chronic HBV infection in this study has been largely unchanged over the past decade among patients in all groups, and overall was 20 times as high as the national population prevalence.

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Phase III Results: Telaprevir, Boceprevir Improve HCV Cure Rates

By: DIANA MAHONEY, Internal Medicine News Digital Network

11/11/10

BOSTON – the forthcoming availability of the protease inhibitors telaprevir and boceprevir for the treatment of chronic hepatitis C is likely to vastly improve virologic response rates and cut treatment times, but experts warn that such advancements need to be balanced against the "huge potential" for misuse of the agents and the need to manage side effects and monitor for antiviral resistance.

When used in combination with standard therapy of pegylated interferon plus ribavirin-based therapy, both of these investigational drugs improved sustained virologic response rates and reduced treatment duration, compared with standard therapy alone, in four pivotal, phase III trials reported at the annual meeting of the American Association for the Study of Liver Diseases.

Telaprevir Boosts Viral Cure Rates

In the ADVANCE trial, a three-arm, double-blind, placebo-controlled study, investigators compared two telaprevir-based regimens with standard therapy in 1,088 treatment-naive patients with chronic genotype 1 hepatitis C virus (HCV) infection, according to lead investigator Dr. Ira M. Jacobson of New York Weill Cornell Medical Center in New York City.

Patients in treatment arms 1 and 2 received 750 mg of telaprevir plus standard therapy for 8 and 12 weeks, respectively, whereas patients in the control group received standard therapy alone, which consisted of 180 mcg/week of pegylated interferon alfa-2a and 1,000-1,200 mg/day of ribavirin.

Patients who achieved extended, rapid virologic response (RVR) – defined as undetectable HCV RNA viral load at treatment weeks 4 and 12 – were treated with standard therapy for an additional 16 and 12 weeks in the 8- and 12-week telaprevir arms, respectively, for a total of 24 weeks, Dr. Jacobson explained. Patients in whom HCV RNA was detectable at either week 4 or 12 received an additional 40 and 36 weeks of therapy, respectively, for a total of 48 weeks, he said. The control group underwent standard therapy for 48 weeks.

Compared with 44% of patients in the control group who achieved sustained virologic responses (SVR) 24 weeks after the last treatment, significantly more patients in both telaprevir arms – 69% of the 8-week group and 75% of the 12-week group – met that end point, Dr. Jacobson reported.

The extended RVR rates in the 8- and 12-week groups were 57% and 58%, respectively, compared with 8% in the control arm, he said.

Significantly improved SVRs were also observed in difficult-to-treat subgroups, according to Dr. Jacobson.

"Among black patients, the [SVR] rates were 58% and 62% in the 8- and 12-week treatment arms, and 25% in the control arm, and in cirrhotic patients the respective rates were 53%, 62%, and 33%," he reported.

Rates of treatment discontinuation due to adverse events, such as rash and anemia, were 8% and 7% in the 8- and 12-week telaprevir groups and 4% in the control group, "which is an improvement, compared with the previously reported profile," he said.

The phase III, open-label ILLUMINATE trial was designed to determine whether extending the telaprevir and standard therapy regimen from 24 to 48 weeks would be beneficial in treatment-naive, genotype 1 HCV patients who achieved extended RVR. In all, 540 patients were initially treated with the 12-week telaprevir regimen described above. Of the 352 patients who achieved RVR, 322 remained on treatment and were randomized to either a 24-week or 48-week treatment arm.

"The [SVR] rates associated with the 24-week and the 48-week arms were statistically similar, at 92% and 87.5%, respectively," reported Dr. Kenneth E. Sherman of the University of Cincinnati. Analyses of the data based on race and extent of liver damage showed that 88% of black patients who experienced extended RVR achieved SVR in both the 24- and 48-week treatment arms, and 82% and 88% of patients with advanced fibrosis/cirrhosis achieved SVR in the 24-week and 48-week arms, respectively, he said.

There were more adverse event–related treatment discontinuations in the longer-treatment group (12.5% vs. 0.6%), suggesting a benefit to the shorter-duration therapy, Dr. Sherman stated. The high viral cure rate observed in the study – the overall SVR rate was 72% in an intent-to-treat analysis – "[supports] the role of response-guided therapy with telaprevir-based regimens" in treatment-naive patients," he said.

Previous Nonresponders Benefit From Boceprevir

Response-guided, fixed-duration therapy with boceprevir was safe and effective in a cohort of HCV genotype 1 patients who were enrolled in the RESPOND-2 study and who failed standard therapy, reported lead investigator Dr. Bruce R. Bacon of St. Louis University. The 403 patients included those in whom prior standard therapy induced no notable decrease in HCV viral load (null responders) or a "not undetectable" decrease in HCV viral load (nonresponders), as well as those in whom prior treatment initially resulted in undetectable HCV RNA, followed by a viral rebound (relapsers), he said.

All the patients underwent a 4-week lead-in phase of standard therapy followed by a random assignment to continue standard therapy alone or in conjunction with 800 mg of boceprevir taken three times daily. The treatment duration for patients in the boceprevir arm with undetectable HCV RNA at study weeks 8 and 12 was 36 weeks, whereas those patients in whom HCV RNA was detectable at study week 8, but undetectable at study week 12, stopped boceprevir at week 36 but continued standard therapy for an additional 12 weeks, for a total treatment duration of 48 weeks, Dr. Bacon said. Patients in the control group were treated for 48 weeks.

The SVR rates at 24 weeks after treatment conclusion were significantly higher in the boceprevir groups, compared with the control group. In the response-guided and fixed-duration boceprevir groups, the SVR rates were 59% and 66%, respectively, compared with 21% in the control patients, he said.

In all study arms, "previous relapsers and previous null responders fared better than prior nonresponders," Dr. Bacon said, noting that the respective SVR rates for previous relapsers, null responders, and nonresponders were 29%, 7%, and 0% in the control group; 69%, 40%, and 33% in the response-guided therapy group; and 75%, 52%, and 34% in the fixed-duration group.

Although the rates of anemia were significantly higher in the boceprevir arms, "the rate of treatment discontinuation related to side effects was similar across all three arms," Dr. Bacon reported, possibly because the use of erythropoietin was allowed to treat anemia, he said.

The findings of this study answer an important question about response-guided therapy "by confirming that many patients can be treated successfully with a treatment duration that is reduced by 3 months relative to the current standard of care treatment," Dr. Bacon said.

Boceprevir with a standard therapy lead-in strategy was also evaluated in the SPRINT-2 study involving HCV genotype 1 treatment-naive patients, according to Dr. Fred Poordad of Cedars-Sinai Medical Center in Los Angeles. The trial included 1,097 patients who underwent a similar 4-week standard therapy lead-in strategy as defined above, followed by the addition of placebo for 44 more weeks or by the addition of boceprevir, either for 24 more weeks for patients with undetectable HCV RNA at week 8 or for 24 more weeks plus 20 additional weeks of standard therapy for patients with detectable HCV RNA at week 8, but not at week 24, Dr. Poordad explained. Patients with detectable HCV RNA at week 24 were discontinued for futility, he said.

"In both the response-guided and fixed-treatment arms, boceprevir increased viral cure rates significantly, by approximately 70%," Dr. Poordad stated. Specifically, the SVR rate was 63% in the 28-week response-guided group, 66% in the 48-week fixed-duration group, and 38% in the 48-week control group, he said.

In a cohort analysis of treatment response for the study’s 159 black patients, the relative improvement in SVR rates remained significantly improved in the boceprevir arms, although the differences were not as robust, Dr. Poordad said. In this subgroup, the respective SVR rates in the response-guided therapy, fixed-duration therapy, and control groups were 42%, 53%, and 23%, respectively.

The rationale for using a lead-in strategy "is to help physicians identify patient responsiveness to interferon before adding boceprevir," Dr. Poordad explained. This can provide an early indication of the likelihood of treatment success. The advantage of subsequent response-guided therapy, he noted, is that it enables physicians to be flexible in managing their patients’ therapy "by adapting treatment duration to individual patient response."

All the sources disclosed relationships with numerous pharmaceutical companies. Among them, Dr. Jacobson and Dr. Sherman disclosed relationships with Vertex Pharmaceuticals, which manufactures telaprevir. Dr. Jacobson also has a relationship with Tibotec, which also is involved with the development of telaprevir. Dr. Poordad and Dr. Bacon also disclosed relationships with Merck, which manufactures boceprevir. Dr. Pockros disclosed relationships with Vertex and Tibotec, which are involved in the development of telaprevir, and Merck, which manufactures boceprevir.

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Potential for Misuse Is ‘Huge’

Dr. Paul J. Pockros

Before next year’s American Association for the Study of Liver Diseases meeting, "we are going to see the approval of two direct-acting antiviral drugs – telaprevir and boceprevir. We anticipate the widespread use of these drugs in the United States and the European Union, as they’ve been shown to improve sustained virologic response rates by approximately 75% in treatment-naive patients," Dr. Paul Pockros said during the meeting. Unfortunately, there is also a "huge potential" for misuse of these drugs, owing to prescribing physicians’ poor understanding of the therapeutic populations, inadequate viral-assay testing, poor side-effect management, and lack of monitoring for antiviral resistance, he said.

The designs of the phase III trials on which the Food and Drug Administration approval will be based, as well as the resulting treatment regimens, are fairly complex, said Dr. Pockros, "so there will be lots of opportunities to screw things up." For example, he hypothesized, "I am sure that some patients are going to be put on telaprevir for 44 weeks with a 4-week pegylated interferon/ribavirin lead-in [even though the lead-in strategy was evaluated for boceprevir, not telaprevir], and other patients might be put on boceprevir for 12 weeks with no lead-in."

For optimal safety and efficacy, Dr. Pockros stressed, physicians must have a good understanding of the treatment regimens, particularly in special populations, and they must actively and frequently monitor for antiviral resistance. Additionally, physicians should anticipate problems with adherence, which is already an issue for some patients on standard therapy, he said, noting that – despite the shorter treatment duration – adding a third drug with its own set of side effects to the mix may not be realistic for patients with a history of poor compliance.

The objective for physicians should be "to keep our eyes on the ball," said Dr. Pockros. "Our primary goal moving forward with all of the new drugs is going to be eradicating the virus."

Paul J. Pockros, M.D., is head of the division of gastroenterology/hepatology and director of the Liver Research Consortium at the Scripps Clinic in La Jolla, Calif. He disclosed relationships with Vertex and Tibotec, which are involved in the development of telaprevir, and Merck, which manufactures boceprevir.

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Specialized Blood Vessels Jumpstart and Sustain Liver Regeneration

ScienceDaily (Nov. 11, 2010) — The liver's unique ability among organs to regenerate itself has been little understood. Now Weill Cornell Medical College scientists have shed light on how the liver restores itself by demonstrating that endothelial cells -- the cells that form the lining of blood vessels -- play a key role.

The results of their study are published Nov. 10 in the online edition of the journal Nature, with a companion study in the Oct. 24 issue of Nature Cell Biology describing how endothelial cells are activated to initiate organ regeneration.

It has long been known that endothelial cells passively conduct blood, passing oxygen, nutrients and metabolic waste to and from tissues through capillary walls. However, in studies published in recent years, the Weill Cornell researchers have demonstrated that endothelial cells actively influence the self-renewal of certain stem cell populations and the regeneration of tissue. Now, these scientists have uncovered the endothelial cells' "instructive role" in liver regeneration. Further, the researchers believe that in the coming years it will be possible to facilitate healing damaged livers by transplanting certain types of endothelial cells with liver cells.

"We have found that specialized blood vessel cells in the liver -- a specific type of sinusoidal endothelial cell -- initiate and sustain liver regeneration by producing growth factors that we have identified. This finding will open the door for designing new therapies to treat damaged livers," says the study's senior author, Dr. Shahin Rafii, who is the Arthur B. Belfer Professor in Genetic Medicine and co-director of the Ansary Stem Cell Institute at Weill Cornell Medical College and a Howard Hughes Medical Institute investigator.

The liver performs many physiological functions, including converting nutrients into essential blood components; storing vitamins and minerals; producing bile for digesting fats; regulating blood clotting; and metabolizing and detoxifying substances that would otherwise be harmful. When the liver malfunctions, the consequences can be grave. Liver failure, due to cirrhosis, various forms of hepatitis, and other diseases, kills some 60,000 Americans per year. But the liver's capacity for regeneration is amazing.

"Until our study, the molecular and cellular pathways that would initiate and maintain liver regeneration were not known," says Dr. Bi-Sen Ding, the study's first author and a senior postdoctoral fellow in Dr. Rafii's lab. "Attempts to transplant hepatocytes [liver cells] directly into the liver led to very limited success. But now we have identified liver sinusoidal endothelial cells (LSECs) -- that, when activated, are critical to liver regeneration and may enable proper engraftment when hepatocytes are implanted into the injured liver."

Dr. Rafii's team determined the mechanism by which LSECs regulate liver regeneration by studying this process in genetically engineered mice whose livers were 70 percent removed. Through a series of experiments involving strategic endothelial cell implantation, the team found that only those LSECs whose genes were producing the angiocrine growth factors Id1 or Wnt2 and "hepatocyte growth factor" (HGF) would initiate and sustain liver regeneration. It is thought that Wnt2 and HGF work together in initiating regeneration, and that the LSECs and the liver cells must be next to each other for successful regeneration were key findings.

"Therefore, to regenerate a long-lasting liver, we may need to co-transplant hepatocytes with the properly activated endothelium, which produces the right growth factors for the hepatocytes to attach, grow and connect with other parts of the liver. Co-transplantation of primed activated endothelium with liver cells may be an important step to design future therapies to regenerate the liver," says Dr. Ding.

Despite these new insights, Dr. Rafii points to an unsolved enigma: How do endothelial cells sense the loss of liver tissue and initiate the regeneration process? "Change of blood flow might be one of the possibilities," suggests Dr. Sina Rabbany, study co-senior author, who is an adjunct professor at Weill Cornell and professor of bioengineering at Hofstra University. "It is well known that endothelial cells can sense subtle changes in the flow of blood because they are located at the interface between the blood flow and vessel wall. The loss of a liver lobe will inevitably alter the local blood flow patterns and resulting shear stresses that are redirected into the remaining lobes. This alteration in the biomechanical transduction process is part of a complex system likely to 'activate' endothelial cells to produce hepatocyte-active growth factors."

Dr. David Lyden, a co-author on the paper and the Stavros Niarchos Associate Professor in Pediatric Cardiology at Weill Cornell Medical College, says, "This is an important study. By targeting endothelial-specific genes such as Id1, as identified in this research, I hope that it will facilitate the design of new therapies to treat people with liver disease, whether due to infection, cancer, or acute or long-term damage."

Earlier this year, Rafii's team developed a new technique and described a novel mechanism for turning human embryonic and pluripotent stem cells into plentiful, functional endothelial cells, which are critical to the formation of blood vessels. The new approach allows scientists to generate virtually unlimited quantities of durable endothelial cells -- more than 40-fold the quantity possible with previous approaches. "These embryonic-derived endothelial cells may provide a useful platform to expand liver and blood stem cells for therapeutic transplantation," states Dr. Zev Rosenwaks, who is a co-author in this study and director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, as well as the director of the Tri-Institutional Stem Cell Initiative Derivation Unit at Weill Cornell Medical College.

"One of the most remarkable findings of our studies is the realization that endothelial cells within each organ are functionally different, and once activated produce a unique set of growth factors," states Dr. Rafii. "The challenge that lies ahead is to discover the organ-specific growth factors produced by the endothelial cells that initiate the regeneration of that particular organ. Then, these factors could be exploited therapeutically to induce selective regeneration of one organ without affecting others."

Additional co-authors include Daniel J. Nolan, Jason M. Butler, Daylon James, Alexander O. Babazadeh and Koji Shido, all of the Ansary Stem Cell Institute in the Department of Genetic Medicine, Weill Cornell Medical College, and the Howard Hughes Medical Institute; Dr. Vivek Mittal, Department of Surgery, Weill Cornell Medical College; and Dr. Thomas N. Sato, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan.

How Vascular Endothelial Cells Renew Blood Stem Cells and Control Stem Cells' Differentiation

Another study by the same group, published in the Oct. 24 issue of Nature Cell Biology, examines how a similar type of sinusoidal endothelial cells that promote liver regeneration also are activated to renew blood stem cells and control their differentiation into various types of blood cells within the bone marrow. The findings may be used to create mass quantities of stem cells following trauma to the bone marrow's microenvironment.

Following injury from therapeutic radiation or chemotherapy, stem cells in the bone marrow are injured, hampering blood cell production. Some patients experience severe and potentially irreversible trauma to their ability to produce blood cells. Until now it has been unclear how the body signals these stem cells to regenerate and to differentiate into cells that form blood cells.

Dr. Rafii and his lab have shown that endothelial cells release specific angiocrine growth factors into the environment of the bone marrow, telling the body to produce more stem cells. The researchers showed that the Akt-pathway is activated in the endothelial cells, which turns on expression of a group of growth factors that induces the bone marrow to produce more stem cells. Following the activation of the Akt-pathway, the MAP kinase pathway is activated, which stimulates the production of angiocrine factors that control the differentiation of the stem cells into various cells needed to make up blood.

Results from the study show a 10-fold increase of stem cell production in mouse models that express higher levels of Akt selectively in endothelial cells, when compared with control mice. If proven applicable in humans, the findings may lead to a new way of treating patients suffering from bone marrow deficiencies.

"You are essentially creating a cell culture bioreactor capable of producing large numbers of stem cells as well as mature blood cells, which can restore bone marrow following trauma," says Dr. Jason Butler, who along with Dr. Hideki Kobayashi is the study's co-first author and senior postdoctoral fellows in Dr. Rafii's lab.

"Using properly activated organ-specific endothelial cells to propagate enough stem and progenitor cells, such as those of bone marrow and liver, so they can be used clinically has broad therapeutic implications not only for regenerative medicine, but also for the study of genetic diseases," concludes Dr. Rafii.

Additional co-authors include Mariko Kobayashi, Bi-Sen Ding, Bryant Bonner, Vi Chiu, Daniel Nolan, Koji Shido, all from Weill Cornell; and Laura Benjamin and Rebekah O'Donnell, from the Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.

The Nature and Nature Cell Biology studies were both supported by grants from the Howard Hughes Medical Institute, the Ansary Stem Cell Institute, the National Institutes of Health, Qatar National Priorities Research Program, the Anbinder Foundation, Newman's Own Foundation, the Empire State Stem Cell Board, and the New York State Department of Health.

Journal References:

1. Hideki Kobayashi, Jason M. Butler, Rebekah O'Donnell, Mariko Kobayashi, Bi-Sen Ding, Bryant Bonner, Vi K. Chiu, Daniel J. Nolan, Koji Shido, Laura Benjamin, Shahin Rafii. Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nature Cell Biology, 2010; 12 (11): 1046 DOI: 10.1038/ncb2108

2. Bi-Sen Ding, Daniel J. Nolan, Jason M. Butler, Daylon James, Alexander O. Babazadeh, Zev Rosenwaks, Vivek Mittal, Hideki Kobayashi, Koji Shido, David Lyden, Thomas N. Sato, Sina Y. Rabbany, Shahin Rafii. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature, 2010; DOI: 10.1038/nature09493

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