Role of ethnicity in overweight and obese subjects with nonalcoholic steatohepatitis (NASH)†

Steatohepatitis and Metabolic Liver Disease


Romina Lomonaco1,5, Carolina Ortiz-Lopez1,5, Beverly Orsak1, Joan Finch1,5, Amy Webb2,5, Fernando Bril1, Christopher Louden3, Fermin Tio4,5, Kenneth Cusi1,5,*,‡DOI: 10.1002/hep.24483

Abstract


The role of ethnicity in determining disease severity in NASH remains unclear. To better understand this, we recruited 152 subjects with biopsy-proven NASH (Hispanics: 63%; Caucasians: 37%). Both groups were well matched for age, gender and total body fat.
We measured:
1) liver fat (LFAT) by magnetic resonance imaging and spectroscopy (MRS);
2) fasting glucose, insulin (FPI) and free fatty acid (FFA) levels;
3) total body fat (TBF) by dual energy x-ray absorptiometry (DXA);
4) liver and muscle (Rd) insulin sensitivity (insulin clamp with 3-[3H] glucose);
5) insulin resistance at the level of the liver (fasting endogenous glucose production derived from 3-[3H] glucose infusion x FPI) and adipose tissue (fasting FFA x FPI).
LFAT was slightly, but not significantly, higher in Hispanics vs. Caucasians (27±2% vs. 24±2%, p=0.16). However, this trend did not translate into worse liver histology (stetaosis, necroinflammation or fibrosis, all NS). Patients with NASH had severe hepatic, adipose tissue and muscle insulin resistance vs. subjects without NAFLD (p<0.01-p<0.0001), but there were no differences between both ethnic groups on these parameters. However, Hispanics vs. Caucasians with T2DM had a trend for worse hepatic/adipose tissue insulin resistance and fibrosis (p=0.052).

Conclusion:

when Hispanics and Caucasians with NASH are well matched for clinical parameters, in particular for adiposity, the slightly higher LFAT content is not associated with worse hepatic insulin resistance or more severe NASH on histology. Hispanic ethnicity does not appear to be a major determinant of disease severity in NASH, although those with diabetes may be at greater risk of fibrosis. Given the higher risk of T2DM in Hispanics, long-term studies are needed to define their risk of disease progression.
(HEPATOLOGY 2011.)

Lawyers and Doctors Agree: Hepatitis C is Likely Curable; Telaprevir-Incivek, Boceprevir-Victrelis

In this program, Dr. Lorenzo Rossaro, Chief of UC Davis Hepatology, introduces a newly FDA approved therapy for Hepatitis C. Series: "UC Grand Rounds"

telaprevir-incivek, boceprevir-victrelis

UBC researchers invent new drug delivery device to treat diabetes-related vision loss

UBC researchers invent new drug delivery device to treat diabetes-related vision loss

A team of engineers and scientists at the University of British Columbia has developed a device that can be implanted behind the eye for controlled and on-demand release of drugs to treat retinal damage caused by diabetes.

Diabetic retinopathy is the leading cause of vision loss among patients with diabetes. The disease is caused by the unwanted growth of capillary cells in the retina, which in its advanced stages can result in blindness.

The novel drug delivery mechanism is detailed in the current issue of Lab on a Chip, a multidisciplinary journal on innovative microfluidic and nanofluidic technologies.

The lead authors are recent PhD mechanical engineering graduate Fatemeh Nazly Pirmoradi, who completed the study for her doctoral thesis, and Mechanical Engineering Assoc. Prof. Mu Chiao, who studies nanoscience and microelectromechanical systems for biological applications.

The co-authors are Prof. Helen Burt and research scientist John Jackson at the Faculty of Pharmaceutical Sciences.

“We wanted to come up with a safe and effective way to help diabetic patients safeguard their sight,” says Chiao who has a family member dealing with diabetic retinopathy.

A current treatment for diabetic retinopathy is laser therapy, which has side effects, among them laser burns or the loss of peripheral or night vision. Anti-cancer drugs may also used to treat the disease. However, these compounds clear quickly from the bloodstream so high dosages are required, thus exposing other tissues to toxicity.

Key to UBC’s innovation is the ability to trigger the drug delivery system through an external magnetic field. The team accomplished this by sealing the reservoir of the implantable device – which is no larger than the head of a pin – with an elastic magnetic polydimethylsiloxane (silicone) membrane. A magnetic field causes the membrane to deform and discharge a specific amount of the drug, much like squeezing water out of a flexible bottle.

In a series of lab tests, the UBC researchers loaded the implantable device with the drug docetaxel and triggered the drug release at a dosage suitable for treating diabetic retinopathy. They found that the implantable device kept its integrity with negligible leakage over 35 days.

They also monitored the drug’s biological effectiveness over a given period, testing it against two types of cultured cancer cells, including those found in the prostate. They found that they were able to achieve reliable release rates.

“The docetaxel retained its pharmacological efficacy for more than two months in the device and was able to kill off the cancer cells,” says Pirmoradi.

The UBC device offers improvements upon existing implantable devices for drug delivery, says Chiao.

“Technologies available now are either battery operated and are too large for treating the eye, or they rely on diffusion, which means drug release rates cannot be stopped once the device is implanted – a problem when patients’ conditions change.”

Pirmoradi says it will be several years before the UBC device is ready for patient use. “There’s a lot of work ahead of us in terms of biocompatibility and performance optimization.”

Team members are also working to pinpoint all the possible medical applications for their device so that they can tailor the mechanical design to particular diseases.

Related topics: diabetic retinopathy, Faculty of Applied Science, Faculty of Pharmaceutical Sciences., health, mechanical engineering, nanoscience and microelectromechanical systems

HCV Advocate Newsletter;Quick Facts about the PI's and Resisting Resistance

July 2011

HCV Advocate Newsletter

In This Issue:

The New HCV Epidemic?

Alan Franciscus, Editor-in-Chief

Quick Facts about the PI's

Alan Franciscus, Editor-in-Chief

HealthWise: Resisting Resistance

Lucinda K. Porter, RN

HCV Snapshots

Lucinda K. Porter, RN and Alan Franciscus, Editor-in-Chief

The Next Wave(s)

Alan Franciscus, Editor-in-Chief

Needle-Exchange Programs Limit Spread of Hepatitis C

By Amy Norton

NEW YORK (Reuters Health) Jun 29 - Programs that give drug users clean needles or safer drug substitutes can cut the spread of hepatitis C, a new study suggests.

In the U.S., most of the roughly 18,000 new infections each year occur when drug users share tainted needles or syringes. Studies have found that clean-needle programs reduce needle-sharing and seem to protect against infection with HIV. The same appears true of programs that get addicts into treatment with methadone.

There has been little evidence that these programs help cut the spread of hepatitis C. But the new findings, published online May 25th in Addiction, suggest that needle and opiate-substitution programs can make a difference in hepatitis C risk, according to senior researcher Matthew Hickman at the University of Bristol in the UK.

Combining the results from six previous studies of UK programs, Hickman's team found that drug users with the highest "coverage" from clean-needle programs were about half as likely to acquire HCV infection as other users.

Among users who said they got enough clean needles to cover all of their injections, just under 4% became HCV-positive. That compared with 7% of drug users who didn't get clean needles for all their injections.

Similarly, the rate of new hepatitis C infection was 3% among drug users who were currently taking an opiate substitute (usually oral methadone), versus 7% among those not on treatment.

Drug users participating in both types of programs fared best of all, with a new infection rate of 2%.

"The implication is that hepatitis C transmission can be reduced by opiate substitution therapy and needle and syringe programs, especially their combination," Hickman told Reuters Health in an email.

While the study looked only at UK programs, it's likely the results would be similar in other countries, he said.

The study has its limits. Its findings are based on observational studies and small numbers. The researchers had usable information on 919 program participants across the six study sites, and there were 40 cases of new hepatitis C infection.

Still, Hickman said the study starts to fill a gap in the knowledge of how well injection drug use programs are working.

SOURCE: http://bit.ly/lMvRUW

Emerging therapies for hepatitis C offer a significant increase in SVR and bring treatment complexity

Hepatitis C Treatment Changing Rapidly With Approvals of Two New Drugs


by Rosemary Frei

On the heels of data presented at the 46th annual meeting of the European Association for the Study of the Liver (EASL) meeting and this year’s Digestive Disease Week meeting came the FDA approval of two new drugs designed to boost the effectiveness of peginterferon-ribavirin therapy for patients with chronic hepatitis C virus (HCV) genotype 1 infection. On May 13, the FDA approved boceprevir (Victrelis, Merck) followed days later by the approval of telaprevir (Incivek, Vertex/Tibotec), marking an eagerly anticipated revolution in the management of patients with HCV.

Cascade of Data

Data on the new drugs have not been in short supply. An article published last year in The New England Journal of Medicine on the use of telaprevir for previously treated patients with chronic HCV genotype 1 infection brought this new class of agents—inhibitors of HCV protease—into the spotlight (McHutchison JG et al. 2010;362:1292-1303). The results of the randomized, double-blind phase II study—known as PROVE3 (Protease Inhibition for Viral Evaluation 3)—indicated that the addition of telaprevir for as few as 12 weeks significantly increased sustained virologic response (SVR).

Two Phase III studies published in March indicated that boceprevir also boosted efficacy in as few as 24 weeks. Results of the RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and Peginterferon/Rebetol 2) trial indicated that the three-drug cocktail nearly tripled SVR rates in previously treated patients (Bacon BR et al. N Engl J Med 2011;364:1207-1217). Furthermore, data from the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial also showed that SVR rates in treatment-naïve patients are boosted significantly with the addition of boceprevir (Poordad F et al. N Engl J Med 2011;364:1195-1206).

Final results from the Phase III REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes) trial also were presented at the EASL meeting. These data included all three major subgroups of patients who were not cured with a prior course of interferon-based therapy, including null responders.

All of the boceprevir studies were paid for by Merck, and the telaprevir studies were sponsored by Vertex and its collaborator, Tibotec.

Stephen H. Caldwell, MD, professor of medicine and director of hepatology, University of Virginia Health System, Charlottesville, pointed out that the emerging therapies for hepatitis C offer a significant increase in sustained viral eradication but also bring treatment complexity, side effects and expense.

“Emerging from the myriad of study names are new monitoring recommendations and prognostic indicators that will take time to really understand,” Dr. Caldwell said. “We should recall that the best-performed studies are closely monitored, often at a level unachievable in clinical practice. Clearly, the field has changed rapidly in a very short period of time. Careful assessment and thoughtful consideration will be key to optimizing success and minimizing failure,” he said.

Boceprevir Trials

In a poster presented at the EASL meeting, John M. Vierling, MD, and colleagues from Baylor College of Medicine in Houston analyzed the relationship between patients’ response during the lead-in period in the boceprevir trials and overall SVR rates. The investigators defined response during the lead-in period as at least a 1.0-log10 reduction in HCV RNA. Data from the SPRINT-2 and RESPOND-2 trials were combined for this study.

The researchers found a steady, stepwise increase in the percentage of patients achieving SVR after at least 24 weeks of triple-agent therapy based on the level of decrease in viral load after the four-week lead-in period with peginterferon-ribavirin alone. The pattern was particularly noticeable among non-black patients. Overall, the advantage of adding boceprevir was greatest for patients with less responsiveness to interferon.

“Patients in the boceprevir arms with a poor response to interferon had sufficiently high rates of SVR as compared with the control group. … [This] dispels concern that the addition of boceprevir to the treatment regimen would be the equivalent of functional monotherapy,” the investigators noted. “However, patients who have a poor response to the interferon may need to be monitored closely to determine who may benefit from better therapies, once they are available.”

They add that conversely, addition of boceprevir may not boost SVR rates among patients with undetectable HCV RNA levels after the lead-in period, but that “in the majority of these patients, total treatment duration is shortened to 28 weeks.”

The four most common treatment-related adverse events (AEs) in the RESPOND-2 and SPRINT-2 studies were fatigue, headache, nausea and anemia. In RESPOND-2, treatment discontinuation due to anemia occurred in 3% of boceprevir patients in 48-week treatment only. None of the controls discontinued due to anemia. The respective numbers for SPRINT-2 were 2%, 2% and 1%. Erythropoietin was allowed for the treatment of anemia at the discretion of the investigators, and in RESPOND-2 was used by 41% and 46% of boceprevir patients in the response-guided and 48-week treatment arms, respectively, compared with 21% of patients in the control arm. In SPRINT-2, the respective numbers were 43%, 43% and 24%. (P values were not supplied.)

Fred Poordad, MD, chief of hepatology and liver transplantation at the Comprehensive Transplant Center at Cedars-Sinai Medical Center in Los Angeles, and lead investigator of the SPRINT-2 trial, gave a talk at the EASL meeting outlining the utility of using an interleukin (IL)-28B polymorphism as a baseline predictor of four- and eight-week response to triple-agent therapy. Dr. Poordad and colleagues from the SPRINT-2 and RESPOND-2 trials examined on SVR rates in patients with three different IL-28B polymorphisms: cysteine–cysteine, thymine–thymine and cysteine–thymine. They determined that the cysteine–cysteine polymorphism is associated most strongly with SVR response; patients with this polymorphism may be eligible for short-duration therapy.

Dr. Poordad’s team also found that lead-in response is a stronger predictor of SVR than any other single baseline characteristic, including IL-28B polymorphism. They concluded that because IL-28B polymorphism status and lead-in response “are powerful predictors of SVR,” the optimal approach may be to use both.

“Taken together, these data showed that the addition of boceprevir to peginterferon and ribavirin achieved significantly higher SVR rates in patients with chronic HCV genotype 1 compared with peginterferon and ribavirin alone, and that nearly half of all patients were eligible to receive a shorter duration of therapy,” Dr. Poordad said.

Telaprevir Trials

The REALIZE trial was a randomized, double-blind, placebo-controlled study of people who were previously treated unsuccessfully for HCV infection.

Subjects were randomized 2:2:1 into two telaprevir-based treatment arms—a “lead-in” arm and a “simultaneous-start” arm—and a control arm, which comprised 48 weeks of treatment with peginterferon-ribavirin alone. The lead-in arm included a four-week lead-in period of treatment with peginterferon-ribavirin followed by the addition of telaprevir for 12 weeks, then followed by 32 weeks of treatment with peginterferon-ribavirin alone. The simultaneous-start arm involved 12 weeks of triple-combination therapy, followed by 36 weeks of peginterferon-ribavirin alone.

Forty-eight percent (316 of 662) of the patients had advanced liver fibrosis or cirrhosis, and 89% (586 of 662) had a high HCV RNA load (≥800,000 IU/mL) at study entry.

The primary end point in all three groups was SVR. The results were analyzed based on three subgroups of patients: patients with undetectable levels of HCV RNA during at least 42 weeks of prior treatment that later became detectable (prior relapsers); patients who achieved at least a 2-log10 decrease in HCV RNA by week 12 of treatment but who did not achieve undetectable levels by week 24 (prior partial responders); and, those who did not achieve a 2-log10 decrease in HCV RNA by week 12 of treatment (prior null responders).

SVR rates for all patients in the telaprevir treatment arms were significantly greater compared with patients in the control group (Table; P<0.001). This held true for patients in the two telaprevir-containing arms combined, among which 86% (245 of 286) of the prior relapsers achieved SVR, 57% (55 of 97) of prior partial responders had an SVR and 31% (46 of 147) of the prior null responders had an SVR.

Click Here Or On Tabel To Enlarge

Table. SVR Rates in the REALIZE Trial

.
“We believe the data showed that an immediate start of a 12-week telaprevir-based regimen substantially improved viral cure rates in all three major subgroups of people who were not cured with currently available medicines,” said Robert Kauffman, MD, PhD, senior vice president and chief medical officer, Vertex Pharmaceuticals.

The most common AEs in the telaprevir studies were fatigue, pruritus, nausea, headache, rash and anemia. Anemia occurred in 36% of patients in the treatment lead-in arm, 30% of subjects in the simultaneous-start arm and 15% in the control arm; erythropoietin treatment was not allowed in the study. Rash was present in 36% of patients in the lead-in arm, 37% in the simultaneous-start arm and 19% of the control arm. Three percent of patients in the telaprevir-treatment arms discontinued all treatment because of anemia and 3% did so because of rash. (No P values were provided.)

Retrospective analyses of IL-28B polymorphisms in patients treated with telaprevir also were presented at the EASL meeting. Data from the ADVANCE (A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir) trial, a Phase III study of treatment-naïve patients with HCV, indicated that the cysteine–cysteine variation of the IL-28B polymorphism is associated with the highest SVR rates, at 90% compared with 73% among patients with the thymine–thymine polymorphism and 71% among individuals with the cysteine–thymine polymorphism.

Retrospective analysis of data from REALIZE indicated that the cysteine–cysteine variant also is associated with the highest SVR rates, at 79% compared with 61% for the thymine–thymine polymorphism and 60% for the cysteine–thymine polymorphism.

Additionally, interim results from a Phase II study of treatment-naïve HCV patients with the combination of telaprevir, peginterferon-ribavirin and the polymerase inhibitor VX-222 (Vertex) also were presented at the meeting. Of patients who received a combination of the four agents, 90% had undetectable HCV RNA after 12 weeks. In another group of patients who received a combination of the four agents with a lower dose of VX-222, 83% showed undetectable levels of HCV RNA.

“Boceprevir and telaprevir will greatly improve our ability to eradicate hepatitis C from both treatment-naïve as well as treatment-experienced patients,” commented Donald M. Jensen, MD, professor of medicine and director of the Center for Liver Disease, University of Chicago Medical Center, who wrote an editorial accompanying the published results of RESPOND-2 and SPRINT-2 (N Engl J Med;2011;364:1272-1274). “However, this success will come at a cost—an increase in side effects and some increase in treatment complexity.”

Series Editor

Tarun Mullick, MD Clinical Faculty Rush-Copley Medical Center Aurora, Illinois

Clinical Staff

Delnor Hospital Geneva, Illinois Provena Mercy Medical Center Aurora, Illinois

Commentary by Dr. Mullick

For the past decade, treatment with pegylated interferon and ribavirin for hepatitis C virus (HCV) genotypes 2 and 3 was able to provide a sustained virologic response (SVR) of approximately 80% after 24 weeks of treatment. However, the more difficult to treat HCV genotype 1 not only requires 48 weeks of treatment with pegylated interferon and ribavirin, but also is associated with an SVR ranging from 40% to 50%.

The problem with pegylated interferon and ribavirin and prior therapies was that they do not target the virus directly in a way that effectively puts the virus in a dormant state. Until now, therapies for patients with HCV genotype 1 infection were limited in their efficacy.

With the arrival of two new HCV protease inhibitors, telaprevir and boceprevir, we now have drugs available that target the virus in a more direct and effective manner. In combination with pegylated interferon and ribavirin, the new protease inhibitors cut the duration of treatment to 24 weeks and achieve an SVR approaching 80%!

The potential for side effects exists for each of the new drugs, with rash and bone marrow–related issues among them. Overall, however, this is the largest breakthrough in hepatitis C treatment in a decade.

By the time other future therapies become available, these medications will likely have treated 80% of patients with HCV infection. These drugs have the potential to dramatically reduce the number of HCV patients who develop cirrhosis, liver cancer and who require liver transplant for this disease.

Fantastic!
--------------------------------------------------------------------------------

Dr. Jensen is on the advisory boards of Merck and Vertex Pharmaceuticals. Dr. Poordad receives consulting fees from Merck, Tibotec and Vertex Pharmaceuticals, among other pharmaceutical companies, and receives grant support and payment for development of educational presentations from Merck.

Turkish scientists develop drugs against Hepatitis C, AIDS

They said medicine against Human Immunodeficiency Virus could prolong lifetime of patients up to 20-25 years by turning AIDS into a chronical disease.

Turkish scientists working in the United States have developed drugs against Hepatitis C and Acquired Immune Deficiency Syndrome (AIDS).

Dr. Ercem Atillasoy and Dr. Dalya Guris, Turkish doctors working at Merck Search Laboratory in Pennsylvania, said the medicine they developed against Hepatitis C achieved full treatment of resistant patients.

They said medicine against Human Immunodeficiency Virus (HIV) could prolong lifetime of patients up to 20-25 years by turning AIDS into a chronical disease.

Atillasoy said the medicine called "Protease Inhibitor" got license from FDA in the United States and expected to get license in Europe soon. He said the treatment aims at eliminating the enzyme preventing reproduction of the virus.

Atillasoy said, "there was no specific medicine against Hepatitis C so far. This medicine directly aims at destroying the disease. A combined modality therapy, like that in cancer treatment, is in question with this medicine. This new medicine increases the success in defeating Hepatitis C after being added to the treatments used so far. "

Atillasoy said there would not be need anymore for liver transplantation with the medicine, this is a milestone in Hepatitis C treatment" he underlined.

Atillasoy also said with a medicine developed against HIV, causing AIDS, the disease would not be fatal anymore but chronical.

"License has been given to the medicine in the United States and in Europe. The medicine prevents virus to enter the DNA of the cell. The medicine does not present full treatment against the disease, it has to be used lifetime." Atillasoy said.

Dr. Dalya Guris of the Merck Research Laboratory said works were also underway to find a vaccine against muscle cancer.

Guris said the medicine would be presented to use within 1-2 years after FDA approval.
http://www.worldbulletin.net/?aType=haber&ArticleID=75785

European Research Consortium wants to develop novel vaccination against hepatitis C

Innovative vaccines with nanotechnology
European Research Consortium wants to develop novel vaccination against hepatitis C
HCVAX is a European joint project that reaches out to develop a vaccine against hepatitis C based on nanotechnology. The German Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung, HZI) in Braunschweig and its department "Vaccinology and Applied Microbiology" is now a part of the transnational consortium with researchers from Germany, France and Switzerland.

More than 170 million people are infected with the hepatitis C virus (HCV) worldwide. Also in Europe this form of hepatitis is a big problem with three per cent of the population affected. The virus is transmitted in operations such as transplantations or by the re-use of syringes for drug usage. Anti-viral treatments are very expensive, have serious side effects and are only effective for some patients. Most of the patients carry the infection for the rest of their lives, with the threat of later developing liver cirrhosis and cancer. Certainly, the most effective way to combat hepatitis C would be a vaccine against the virus – but to date no efficacious vaccine exists.

"We will pursue a completely new approach to develop a HCV vaccine," says Prof. Carlos A. Guzmán, head of the Vaccinology Department at the HZI. With the help of innovative, biocompatible nanogels part of the genetic information of the virus is brought into the body by so-called "RNA replicons". The synthetic nanogels have a diameter of only a few nanometres and are composed of a biopolymer matrix. Immune cells will take up the nanogels with the genetic information and will produce harmless components of HCV. The immune cell then responds to those foreign structures and will generate memory cells: with this, the vaccination would be successful and from then on one would be protected against an infection with pathogen HCV.

By using novel drug amplifiers, so-called adjuvants, the immune response shall be more efficient and targeted. "The HZI has a long-standing expertise in this field. We will incorporate this knowledge into the project to develop more effective vaccines," says Guzmán. "We want to identify those adjuvants that are most eligible for a use in the nanogel composition. The targeted transport to certain defence cells shall guarantee an optimal immune response."

To exclude side effects, potential vaccine candidates have to be tested in several systems. Promising structures will then be selected for further clinical development.

The consortium consists of two companies, three academic institutions and one clinic. They combine their expertise on the field of nanotechnology, biochemistry, immunology, vaccine development and clinical research. "Beyond that we expect that these novel vaccination strategies can be expanded onto the clinical management of other diseases," says Guzmán.

Funding is granted for the next three years from the "EuroNanoMed Joint Transnational Initiative" of the European Union. The German Ministry for Research and Education is funding the project in Germany.

The Partners:

Federal Department of Economic Affairs (Eidgenössisches Volkswirtschaftsdepartement), Mittelhäusern, Switzerland (coordinator)

Medipol SA, Lausanne, Switzerland

Institut Pasteur, Paris, France

Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung GmbH), Braunschweig, Germany

EDI GmbH, Reutlingen, Germany

Hôpital Cochin, Paris, France