February 6, 2012

Coffee Lowers Liver Fibrosis Risk in Certain Patients

Laura Newman, MA

February 6, 2012 — Drinking caffeinated coffee protects against liver fibrosis in patients with nonalcoholic fatty liver disease, according to research published in the February issue of Hepatology.

In introducing the study, Jeffrey C. Molloy, MD, from the Division of Gastroenterology and Hepatology, Wilford Hall Medical Center, Lackland Air Force Base, Texas, and coauthors refer to previous research linking coffee with decreased progression of liver fibrosis in patients with alcoholic cirrhosis, cirrhosis in general, and elevated liver enzymes. "This news is significant," they write, "because any modality that decreases the progression of fibrosis in chronic liver disease, especially if it confers few adverse effects, has the potential to improve morbidity and mortality."

In summing up the import of their findings, they add: "Moderate coffee consumption may be a benign adjunct to the comprehensive management of patients with [nonalcoholic steatohepatitis (NASH)]."

However, Arthur L. Klatsky, MD, from the Kaiser Permanente Northern California Division of Research in Oakland, pins more benefit on "avoiding risk factors, such as obesity, high alcoholic intake, and viral hepatitis," he told Medscape Medical News. "In my opinion, these are much more important than suggesting that people drink moderate amounts of coffee."

He continued: "I don't think that the public should be advised to drink coffee." Dr. Klatsky was not involved in the present study, but he was the lead author of the first paper linking coffee intake to cirrhosis, published in 1992.

The new finding comes from a validated caffeine questionnaire administered to 4 patient groups at the Brooke Army Medical Center Hepatology Clinic in Fort Sam Houston, Texas: negative controls, bland steatosis/not-NASH, NASH stage 0 to 1, and NASH stage 2 to 4. Between March 2010 and March 2011, 306 patients completed the caffeine questionnaires, which also tabulated tea drinking. Overall, coffee drinking accounted for 71.5% of all caffeine consumed. Patients were also questioned about their intake of other caffeinated beverages, such as various teas, cocoa, caffeine-fortified drinks, chocolate, and caffeine pills. No other caffeinated beverages showed a correlation with any dimension of liver protection (eg, NASH, insulin resistance, diabetes, liver enzymes).

Patients with no to early fibrosis received 57.5% of their caffeine from regular coffee, in comparison with those with advanced fibrosis, who consumed only 35.9% of their caffeine from coffee (P = .041). Average caffeine intake varied significantly across the 4 groups on analysis of variance (P = .024). Coffee intake specifically varied between the 4 groups (P = .011).

The authors flagged the finding that patients with bland steatosis/not-NASH and control patients drank less coffee than those patients with NASH/steatosis. They speculate: "It may be that coffee is only beneficial to those [patients with nonalcoholic fatty liver disease] with a propensity for fibrosis (i.e., NASH patients)."

The authors acknowledge several limitations to their analysis; namely, that their study "was not prospective and thus did not follow the effects of differences in fibrosis on clinical outcomes over time," as well as a lack of blinding of the interviewers. They advise further study of the specific components of coffee and their effects on metabolic activities of the liver.

The study's senior author has disclosed that he consults for Amylin. Dr. Klatsky and the other authors have disclosed no relevant financial relationships.

Hepatology. 2012;55:429-436. Abstract


New Study of Interferon-free HCV Therapy Hailed as 'Watershed Moment' in Hep C Research


Gastroenterology & Endoscopy News


SVR Achieved With Two Direct-acting Antivirals in Absence of Interferon in Small Study

A combination therapy including two investigational direct-acting antiviral agents (DAAs)—asunaprevir and daclatasvir—suppressed hepatitis C virus (HCV) genotype 1 infection in a majority of patients who had previously not responded to treatment, according to results from a small Phase II study published in the Jan. 19 issue of The New England Journal of Medicine (Lok AS et al. 2012;366:216-224).

Success rates were 100% in patients who received the drugs in combination with peginterferon alfa-2a (Peg-IFN) and ribavirin (RBV).

And, most notably, even in patients who received daclatasvir and asunaprevir without Peg-IFN and RBV, sustained virologic response (SVR) was achieved in 36% of patients, making this the first published study to show that SVR can be achieved with an IFN-free treatment in previous null responders.

“The response in some patients to the combination of daclatasvir and asunaprevir alone showed proof-of-concept that a sustained virologic response can be achieved without peginterferon and ribavirin therapy,” concluded the research team, led by Anna S. Lok, MD, professor of internal medicine in the Division of Gastroenterology, University of Michigan Medical School, Ann Arbor.

In an editorial accompanying the study, Raymond T. Chung, MD, director of hepatology and medical director of the liver transplant program at Massachusetts General Hospital, Boston, called the study a “watershed moment in the annals of HCV therapy.

“It shows that sustained virologic response can be achieved without interferon. Implicit in this finding is the concept that two potent agents with complementary resistance profiles, given for a sufficient duration, can impose a stranglehold on viral replication and result in clearance of the virus.”

In this Phase II study, 10 patients received the experimental drugs in combination with Peg-IFN and RBV for 24 weeks. All 10 patients had undetectable viral loads at the end of treatment and at 12 weeks after stopping treatment. Nine patients continued to exhibit SVR at 48 weeks after treatment, whereas one patient had HCV RNA of less than 25 IU/mL at post-treatment week 48 and undetectable HCV RNA 13 days later.

In a separate arm of the study, 11 patients received asunaprevir and daclatasvir alone, without the addition of Peg-IFN and RBV.

Of these, four patients (36%) achieved an SVR at 12 and 24 weeks after treatment. Six patients (55%) had viral breakthrough during treatment, with resistance mutations to both antiviral agents. Breakthroughs occurred as early as treatment week 3 and as late as treatment week 12.

Although only one-third of the patients given the two-drug combination without Peg-IFN and RBV achieved an SVR, investigators and other hepatologists say the finding is “very promising.”

“For years, the concept of IFN-free therapy was hotly debated. Now, we’re very quickly moving toward IFN-free therapy. It’s potentially just around the corner,” said Donald M. Jensen, MD, professor of medicine and director of the Center for Liver Diseases, University of Chicago Medical Center.

“For patients who can wait, they might just have to wait a few more years until IFN-free therapy is on the market,” he said.

Daclatasvir is a first-in-class, highly selective HCV NS5A replication complex inhibitor that has shown picomolar potency in vitro. Asunaprevir is a highly active HCV NS3 protease inhibitor. Both drugs produce robust declines in HCV RNA levels in patients with HCV genotype 1 infection and, taken in combination, there is no clinically meaningful pharmacokinetic interaction.

Hepatologists say that treatment of HCV infection is entering a new era, highlighted by combinations of second-generation DAAs. As more DAAs are developed with non-overlapping resistance profiles, they may reduce dependence on treatment with IFN.

“These data are very encouraging because peginterferon-alfa and ribavirin are associated with many side effects and many patients with hepatitis C choose not to receive treatment for fear that they cannot tolerate those drugs,” said Dr. Lok, in a statement.

The participants in Dr. Lok’s study had previously failed to respond to Peg-IFN and RBV treatment, meaning they represent a difficult-to-treat population with poor expected outcomes. Previous null responders typically do not respond to retreatment with Peg-IFN and RBV and also tend to have a poor response to triple-combination therapy with Peg-IFN and RBV plus a protease inhibitor.

This combination of new DAAs, if supported by larger studies, could help the large number of patients who have not responded to previous treatment.

“Because of this high unmet medical need, there is a necessity for new combination regimens that can increase response rates in that population,” said Dr. Lok.

Study Details

In the current study, investigators screened 56 patients and ultimately enrolled 21 patients in an exploratory cohort to assess the safety and antiviral activity of the new DAAs. All patients were between the ages of 18 and 70 years, had a chronic HCV genotype 1 infection with an HCV RNA level of 105 IU/mL or higher, showed no evidence of cirrhosis and exhibited no response to previous HCV therapy. Of these patients, 90% had interleukin 28B (IL28B) genotype CT or TT, both of which are associated with poor response to Peg-IFN and RBV, and most patients had HCV genotype 1a infection.

Daclatasvir was administered orally at a dose of 60 mg once daily and asunaprevir at a dose of 600 mg twice daily, with no dose reductions permitted. Ten patients also received Peg-IFN 180 mcg per week, administered subcutaneously, and RBV, administered orally twice daily, with doses determined according to body weight.

Investigators believe that the combination of two DAAs increases the resistance barrier, particularly for patients with HCV genotype 1b infection. In this study, all viral breakthroughs occurred in patients with HCV genotype 1a infection.

This study appears to confirm the results of a recent Japanese study, which showed a high SVR rate among patients with HCV genotype 1b infection in a pilot study of 10 previous non-responders who received combination therapy with asunaprevir and daclatasvir (Chayama K et al. Hepatology 2011 Oct 10; 10.1002/hep.24724 [Epub ahead of print]).

The key benefit of treatment with Peg-IFN and RBV appears to be prevention of viral breakthrough. No patient who received the four-drug combination in the current study experienced a viral breakthrough, whereas six patients in the group that received the DAAs alone had viral breakthroughs. All patients who had a viral breakthrough received and initially responded to Peg-IFN and RBV as rescue therapy. Most ultimately had therapeutic failure.

The high frequency of resistance sends a strong cautionary note about these therapies, said investigators. Future studies of combinations of DAAs without Peg-IFN and RBV in patients with HCV genotype 1a infection should proceed carefully, said the investigators.

But, they added, further research on combinations of DAAs, with or without Peg-IFN and RBV, should be encouraged.

The most common adverse events in this study were diarrhea, fatigue, headache and nausea, which were mild or moderate in all cases. Grade 3 or 4 neutropenia occurred in six patients, all of whom were receiving Peg-IFN and RBV in addition to the two DAAs. No grade 3 or 4 events related to hemoglobin levels or platelet counts were observed.

“This is an exciting study that means care will be better for patients,” said Andrew J. Muir, MD, clinical director of hepatology, Duke University Health System, Durham, N.C., who was not involved with the study.

“For the first time, patients were cured of HCV without interferon-a. Interferon-a has always been the backbone of HCV therapy but has many side effects that make treatment too difficult for many patients.”

Bristol-Myers Squibb, manufacturer of asunaprevir and daclatasvir, funded this study. Dr. Lok has received consulting fees from Abbott Laboratories, Bristol-Myers Squibb and Gilead Sciences, and grant support from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck–Schering-Plough and Roche. Dr. Muir has received grant support from Bristol-Myers Squibb, Gilead Sciences, Merck–Schering-Plough, Roche and Vertex Pharmaceuticals. Dr. Jensen has served on advisory committees or review panels for Abbott Laboratories, Boehringer Ingelheim, Genentech/Roche, GlobeImmune, Human Genome Sciences, Merck, Pfizer, Pharmasset, Tibotec and Vertex Pharmaceuticals; he has received consulting fees from Abbott Laboratories, Bristol-Myers Squibb, Genentech/Roche and Vertex Pharmaceuticals; and he has received grant/research support from Boehringer Ingelheim, Genentech/Roche, Tibotec and Vertex Pharmaceuticals.


Aged-Based Hepatitis Screenings on the Horizon

Posted by Dr. Stephen Vogt ⋅ February 6, 2012

Deaths due to hepatitis C in the United States have already reached 15,000 deaths each year, according to the Centers for Disease Control and Prevention (CDC). This number is expected to rise to 35,000 hepatitis C deaths per year within the next two decades. Baby Boomers account for 75 percent of hepatitis C virus (HCV) fatalities.

An estimated 1.6 million U.S. adults ages 40-64 are currently infected with the hepatitis C virus but have no idea of their disease state. How could this happen? The answer is partly due to the silent nature of HCV infection: it can be without any symptoms for up to 20 years. The other part of the answer is connected to the current standards that limit HCV screenings to those with conventional high risk factors (such as IV drug use, blood transfusion before 1992, or unprotected sex with a known HCV-infected person). Yet a huge portion of people (many of them Baby Boomers) do not fit this risk factor profile.

As I pointed out last year, in “Call for Wider Hepatitis Screenings ,” we can stem this rising tide of HCV deaths by instituting more HCV screenings, particularly age-based screenings for all Baby Boomers. Today, we are getting one step closer to changing the HCV screening process from the current one based on risk factors to a screening process based on birth year.

The CDC is poised to recommend a one-time age-based screening for all Baby Boomers. A new CDC-funded study took a close look at the cost-effectiveness of an aged-based screening for HCV. It was clear that a one-time screening (followed by treatment for infected individuals) for everyone born from 1945-1965 would pay off both financially and in healthier lives. The cost-effectiveness from widespread HCV screenings would be in line with cervical cancer and cholesterol screenings.

A switch to an aged-based screening couldn’t come at a better time. Screening tests are faster and easier than ever (answers can come back as quick as 20 minutes ) and treatments today clear this virus in greater numbers of infected people, giving a meaningful cure to most patients.

Stephen C Vogt, PharmD
President and CEO
BioPlus SP


Rein DB, Smith BD, Wittenborn JS, et al. The Cost-Effectiveness of Birth-Cohort Screening for Hepatitis C Antibody in U.S. Primary Care Settings. Ann Intern Med November 4, 2011 [epub ahead of print]. Highleyman L. AASLD: Deaths Due to Hepatitis C Now Exceed HIV Deaths. Report from the American Association for the Study of Liver Diseases Liver Meeting. November 15, 2011.


Spinal Cord Stimulation Effective for HIV Neuropathy

Kate Johnson

February 6, 2012 (Miami Beach, Florida) — Constant spinal cord stimulation delivered through a permanently implanted device can offer pain relief to patients with HIV-related polyneuropathy that is refractory to conservative treatment, according to Kenneth Candido, MD, and colleagues. Results were presented in a poster here at the 6th World Congress of the World Institute of Pain.

"We believe that it is not only a new indication, but it offers relief for individuals who were previously left to the devices of primary care physicians who really only have at their disposal the ability to prescribe narcotic analgesics," Dr. Candido, who is chair and professor in the Department of Anesthesiology at Advocate Illinois Masonic Medical Center in Chicago, told Medscape Medical News in an interview during the meeting.

Spinal cord stimulation is a well-established technique currently indicated for the management of failed back surgery syndrome, complex regional pain syndrome, inoperable peripheral vascular disease, and refractory angina pectoris, Dr. Candido and colleagues report.

To date, the team has used the technique in 6 patients with debilitating pain from HIV-related polyneuropathy. The first case is described in the poster.

The patient, a 50-year-old man with a 20-year history of HIV, was receiving highly active antiretroviral therapy (HAART). He had an 8-year history of "excruciating" pain.

"He had ongoing severe peripheral neuropathic pain and burning allodynia in both feet, primarily the plantar surfaces. He had not responded to conservative management, which had included high doses of opioid analgesics, anti-inflammatory medications, antiepileptic drugs, and other adjuvants such as peripheral nerve block therapies and epidural injections," said Dr. Candido.

The syndrome of HIV-related pain tends to have a distal "stocking" distribution in the lower extremities, similar to diabetic peripheral neuropathic pain, he explained. "It has been almost exclusively related to pain below the knees. It tends to be bilateral, and we suspect that the mechanism is similar to diabetic peripheral neuropathic pain, in that there is microvascular disruption either due to the virus attacking the vasculature or, alternatively, due to the HAART therapy, which may have a predisposition for the small blood vessels."

After the patient underwent a trial of temporary spinal cord stimulation, in which 2 eight-electrode leads were advanced into the dorsal epidural space and fluoroscopically guided to T9–T10, with good results, a permanent implant was placed.

"He has now had almost 2 years of reduction in his pain, from a constant level of about 8 out of 10 down to about 1 or 2 out of 10, and we've been able to wean him off his opiate analgesics," said Dr. Candido.

On the basis of this initial experience, 5 other HIV patients have received permanent implants, with similar success.

"The beauty of neuromodulation is that we can tailor therapy to the patient's individual symptoms. While I would say that we've used a lumbar approach and lower thoracic stimulators in all patients, clearly not every individual is exactly alike, so we choose our criteria very carefully and we select the actual placement of the stimulators based on the concordant response that we identify during the trial process. We've individualized it, but by and large every individual has responded favorably to T8 through T10 placement of these electrodes."

Dr. Candido explained that as HIV patients live longer because of HAART, the medical community must find pain relief options that are superior to opiate analgesics, which have the potential for extensive adverse effects, including nausea, vomiting, pruritis, constipation, urinary retention, and respiratory depression.

His group has also permanently implanted continuous intrathecal drug delivery systems in 4 HIV patients who did not want spinal cord stimulators.

"Dorsal column stimulation and/or intrathecal delivery of opioids and adjuvants proves to be the primary modality that we believe should be used as a first-line therapy once individuals are identified with this peripheral neuropathic pain process," he said.

Despite the immunocompromised state of HIV patients, he said no adverse events have been reported.

"We know that individuals who have compromised immune status are always predisposed to...infectious processes.... Infections are found in 1% to 2% of individuals who have a dorsal column stimulator, but...in almost two-and-a-half years, we have not identified any superficial or deep infections associated with the permanent implantation process."

Before proceeding, his group studied the orthopedic literature looking at infection rates among HIV patients with hip and knee replacements. "We haven't seen an increase in the incidence of infection in those individuals, so we extrapolated the orthopedic data to our own neurological/surgical population and found that it was logical and intuitive that we should also not have a high level of systemic infection or even localized infection if we took all the appropriate precautions."

Dr. Candido has disclosed no relevant financial relationships.

6th World Congress of the World Institute of Pain: Abstract 171. Presented February 5, 2012.


Liver cirrhosis curable (???)


© Photo: ru.wikipedia.org

Olga Pshenitsyna Feb 5, 2012 16:52 Moscow Time

Russian scientists at the Pharmacology Institute of the Russian Academy of Sciences Siberian Department have developed a unique medication for liver cirrhosis. It is based on a chemical compound that has absolutely no analogues in the world.

Up to now, liver cirrhosis has been deemed as an utterly incurable disease. But the pharmaceutical drug created by Tomsk and Novosibirsk scientists can work wonders for cirrhosis patients. The scientists have been working on this substance for 10 years and their efforts have finally been rewarded. The specific effects of the new medication in the treatment of liver cirrhosis have been experimentally confirmed, while toxicology tests have proven that it is toxic-free, Professor Gleb Zuzkov told reporters this week:

"Experiments on animals have shown that the substance has high hepa-protective efficiency during various chronic liver diseases, including the initial stages of cirrhosis. What’s more, despite being a protein-based ferment, it has no toxic effects."

The use of electron beam synthesis nanotechnology in the drug’s creation helped obtain unique properties needed to stimulate effective regeneration of liver tissue through stimulating the patient’s own stem cells capable of restoring healthy tissue in a damaged liver. Professor Zuzkov:

"Our medicine has no analogues either among the existing drugs or the ones that are only just being developed. No other substance that has been described in scientific literature so far can boast such a pronounced effect on progenitor cells and their regulation mechanisms as ours."

The wonder medication is currently undergoing pre-clinical tests. The follow-up clinical testing and registration formalities may take around five years.