Wednesday, December 14, 2011

Hepatitis News Ticker- Telaprevir and Boceprevir

Advance Liver Disease
Patients with advanced fibrosis need to be regularly monitored for evidence of decompensated disease, and complications need to be aggressively managed.
Audio Advanced Liver Disease: What Every Hepatitis C Virus Treater Should Know

Fatty Liver Disease
Conventional LFTs May Miss Fibrosis in Type 2 Diabetes

In Case You Missed It
Fever-Oral Temperature Changes After Initial Peginterferon Alfa-2a Injection in Chronic Hepatitis C Patients Reflect Host-Inteferon Responsiveness

Dec 2011-Improving the Recognition and Diagnosis of Fibromyalgia

Telaprevir and Boceprevir


2 Adherence Studies- Telaprevir & Boceprevir

HepDart: Quantification of the Effect of Adherence to Clinical Outcomes in Telaprevir-based Regimens

EASL: Adherence To Assigned Dosing Regimen and Sustained Virologic Response Among Hepatitis C-Genotype 1 Previously Untreated and Peginterferon/Ribavirin Treatment-Failure Patients Treated With Boceprevir Plus Peginterferon Alfa-2b/Ribavirin (patients with >80% adherence to all dosing achieved 90% cure rates. My guess is if adherence is 100% SVR rates will be higher)

Journal of Clinical Virology

Dynamic changes in HCV RNA levels and viral quasispecies in a patient with chronic hepatitis C after telaprevir-based treatment

Academic Medical Center, Department of Gastroenterology and Hepatology, Amsterdam, The Netherlands

Received 28 July 2011; received in revised form 8 November 2011; accepted 11 November 2011. published online 06 December 2011.
Corrected Proof


Telaprevir is a selective inhibitor of the hepatitis C virus NS3·4A serine protease. Treatment with telaprevir resulted in a rapid HCV-RNA decline in chronic hepatitis C genotype 1 patients.


To report the clinical and viral course of a patient treated with telaprevir in combination with pegylated interferon-alpha-2a and ribavirin in a Phase 2 clinical trial (PROVE3).

Study design

This previous non-responder to interferon based therapy was treated for 40 weeks with a telaprevir, pegylated interferon alpha-2a, and ribavirin regimen. Viral sequencing and phylogenetic analysis were performed before, during and after therapy.


The patient, a 54 years old male patient, experienced a viral relapse 4 weeks post-treatment and HCV-RNA levels continued to increase 14 weeks post-treatment (150,000IU/mL). The viral population, which was wild type at baseline, consisted of only V36A variants at both of these post-treatment timepoints. Subsequently, this patient had a transient disappearance of HCV-RNA for more than 1 year in the absence of antiviral therapy. Thereafter, HCV-RNA reappeared again with a viral population consisting of only wild type virus. Phylogenetic analysis of NS3·4A corresponded with a viral population bottleneck resulting in changes in viral quasispecies.


In this case report, significant viral load reductions resulted in a genetic bottleneck leading to a reduction of variability in the hepatitis C viral population. We hypothesize that the reduction in viral heterogeneity potentially led to a reduced viral capacity to adapt to a host immune response leading to a transient loss of detectable HCV-RNA.

BI 201335-BI207127

Efficacy of the Protease Inhibitor BI 201335, Polymerase Inhibitor BI 207127, and Ribavirin in Patients With Chronic HCV Infection - pdf attached

Depressive symptoms influence treatment course among Hep C patients
The most recent issue of the American Journal of Gastroenterology investigates changes in depressive symptoms and the impact on treatment course among Hepatitis C patients undergoing interferon-α and ribavirin therapy.

Accounting for severity of depressive symptoms at baseline, Dr Megan Oser and colleagues from California, USA describe depressive symptom change over the course of antiviral treatment among patients with hepatitis C virus (HCV), and the relationship of such symptom change to treatment duration and response.

Depressive symptoms, measured with the Beck Depression Inventory (BDI), were examined prospectively among 129 HCV patients who endorsed minimal, mild, or moderate depressive symptoms prior to commencement of antiviral therapy.

Assessments were obtained at baseline, 2 weeks, 4 weeks, and thereafter at 4-week intervals until treatment was discontinued or completed.

The research team found that average depression score of the participants prior to commencing treatment was 7.4.

Depressive symptoms may worsen during antiviral therapy
American Journal of Gastroenterology
The team observed that depressive symptoms increased over the course of treatment, with average scores of 13 at the final assessment at the end of treatment.

The researchers observed that patients with mild depressive symptoms at baseline demonstrated the greatest increase, and the greatest change in depressive symptoms from baseline to treatment completion.

The team noted that patients who were minimally depressed at baseline completed the least amount of treatment.

Likewise, minimally depressed patients were less likely than mildly and moderately depressed patients to attain an antiviral treatment response.

Dr Oser's team concluded, "Depressive symptoms may worsen during antiviral therapy among patients with HCV."

"Notable changes in patients with subclinical depressive symptoms at baseline may be of significant concern, as the present work suggests that their depressive symptom changes are the most unstable."

"Thus, findings suggest that the degree of within treatment symptom change may be a more useful predictor of ability to tolerate treatment."

"As the findings of the present study are preliminary, we urge further research and replication before drawing firm conclusions."
Am J Gastroenterol 2011; 106:2123–2132



Alarming Incidence of Hepatitis C Virus Re-infection After Treatment of Sexually Acquired Acute Hepatitis C Virus Infection in HIV-infected MSM

Femke A.E. Lambers; Maria Prins; Xiomara Thomas; Richard Molenkamp; David Kwa; Kees Brinkman; Jan T.M. van der Meer; Janke Schinkel

Discussion Only

Click Here For Full Text

With this study, we demonstrate an alarmingly high incidence rate of sexually transmitted HCV re-infection among HIV-infected MSM previously successfully treated for primary HCV infection.

Most importantly, these findings stress the importance of repeated risk counselling for HCV transmission which should be provided not only before and during treatment but also after its completion. MSM re-infected with HCV showed higher rates of noninjecting recreational drug use. Sexual risk behaviour, including recreational drug use during sex, was highly prevalent (data not shown). Unfortunately, because of our relatively small study population with behavioural data, we were not able to examine risk behaviour more precisely and longitudinally.

The high incidence rate in this study implies that ALT levels, which can be elevated during an acute HCV infection, should be measured regularly in this population. Because these levels are not always elevated during acute infection or might not coincide with the test moment, as shown in Fig. 3, subsequent HCV RNA testing, especially in cases of high-risk behaviour, should be performed regularly, as antibodies remain in general present after successful treatment.

Along with risk behaviour, the role of biological susceptibility to HCV re-infection, although still unclear, is an important consideration. Importantly, discussion is ongoing whether previous infection with HCV can generate partial protective immunity to re-infection or increase the chance of clearance of re-infection.

Several studies that compared incidence rates of primary infection and re-infection among IDUs have presented results that argue both for[8,18,19] and against[6,7,10] this phenomenon. Differences between these studies are probably due to variations in intervals of testing, age of the participants, frequency of ongoing drug use and adjustment for behaviour in the analyses. The higher incidence of re-infection in our study compared with the incidence of primary infection in Amsterdam[2,20] and elsewhere[3] indicates that, as expected, there is no complete protection. Yet, the finding that most re-infections in this study occurred with a different genotype compared with the primary infection suggests that genotype-specific immunity may develop in some individuals.

Additionally, underlying a persons' ability to develop protective immunity, genetic profiles may play a role in susceptibility to HCV re-infection. The association of genetic variations near the interleukin-28B (IL28B) region with spontaneous HCV clearance and treatment-induced clearance has been well described for HCV-mono-infected patients.[21–28] Similar results have been found regarding HCV treatment response in persons co-infected with HIV, although in this population the association is less clear for those treated during the acute infection.[29–34] The effect of IL28B polymorphisms on HCV re-infection has not been described. In accord with the effects in primary infection, one would expect the responder genotype to be at least more likely to allow clearance of re-infection than the nonresponder genotype. Whether initial partial protective immunity is also more established in individuals with a beneficial IL28B genotype remains undetermined.

Apart from HCV-specific immune responses, HIV co-infection may play an important role. The exact role of HIV co-infection in primary sexually transmitted HCV infection is not well known. CD4 cell depletion in the gut may diminish the immune response against HCV sexual transmission.[35] Nevertheless, CD4 cell counts did not differ between patients with and without re-infection, indicating that the level of immune suppression caused by HIV co-infection does not influence the risk of re-infection following successful HCV treatment.

The results of this study may lead to a change in the current definitions of HCV relapse and re-infection. When no further genotyping or sequencing is performed, a recurrent HCV viraemia within 6 months after a negative test at the end of the treatment is currently considered a relapse.[36] Our study demonstrates that early recurrence of HCV could well be a re-infection with another genotype or strain. This distinction has important clinical ramifications and should, therefore, be recognized by clinicians. The definition of relapse or re-infection, especially in population with a high incidence of infection, should, therefore, always be based on virological characteristics and not on a specific interval between the end of treatment and recurrence of HCV RNA in the serum.

Finally, from a clinical and cost-effective perspective, the results of this study will encourage discussion about the validity of repetitive HCV treatment in patients with numerous subsequent re-infections owing to continued risk behaviour.

Apart from small numbers, this study has other limitations. We have not studied the possible existence of HCV-mixed infections during primary infection. Therefore, we cannot entirely exclude the possibility that re-infections were previously existing infections that became detectable after a dominant strain had been cleared.[37] However, the fact that the median interval from the first HCV RNA-negative test to the first HCV RNA-positive test after treatment was 8 months, with several negative results in between, strongly suggests that all re-infections were recently transmitted infections.

Furthermore, as this was not a prospective study, time between tests was not similar for all patients, and a re-infection followed by a quick, spontaneous clearance might have been missed. Nevertheless, as the median time between tests was 3 months, we do not expect this to have significantly influenced the incidence rate.

In conclusion, a high incidence rate of HCV re-infection among HIV-infected MSM in Amsterdam was demonstrated in this study, emphasizing the need for more extensive risk behaviour counselling and secondary prevention by regular and frequent HCV testing in this population. Future research should focus on the reasons for continuing high-risk sexual behaviour in order to improve targeted prevention. In addition, research should try to elucidate the virological and host factors associated with re-infection and its outcome in HIV-infected individuals.

Coinfection with hepatitis B virus (HBV) nearly doubled the risk of progression to AIDS or death among people recently infected with HIV...

DEAR DR. DONOHUE: My husband and I are in our 50s. Both of us had an exam this year from different doctors. Blood tests showed that we both have hepatitis C. Neither of us feels sick, and neither of us ever remembers acquiring this infection. Our doctors say we don't need any treatment. What is the treatment if we ever do? Are we infectious to others? We don't have children. -- K.K.

ANSWER: In North America, hepatitis B and C are the two most common kinds of viral hepatitis. In the United States, about 1.25 million are infected with hepatitis B virus. Five percent of infected people go on to develop a chronic infection, one in which the virus remains in the liver, and these people face the possibility of coming down with liver cirrhosis or liver cancer. A vaccine for the prevention of hepatitis B is available.

Hepatitis C infects around 3 million Americans. In contrast with hepatitis B, around 70 percent to 80 percent will have a chronic infection. A sizable number will come down with liver cirrhosis or cancer, but that doesn't happen right away. It takes 20 or more years before those complications arise.

When treatment of hepatitis C is advised, two medicines have been given simultaneously for many years. Those drugs are peginterferon and ribavirin. About 50 percent of chronic hepatitis C patients respond well to this regimen. However, blacks have a poorer response, with only 25 percent achieving viral suppression. A true breakthrough has arrived in the treatment of hepatitis C. Two new drugs, telaprevir (Incivek) and boceprevir (Victrelis) have had a huge impact in improving treatment success. Either of these drugs, given in conjunction with the standard treatment of ribavirin and peginterferon, greatly increases the cure rates for blacks and whites.

An initial sickness after acquiring hepatitis C virus is rare, and, that's why you and your husband didn't realize you were infected. The virus can be transmitted through blood transfusions (no longer a threat), sharing needles for drug injections, rarely through sexual relations and household contact, but more possibly through promiscuous sex and in ways yet to be determined. You're not a threat to others.

The booklet on hepatitis describes these infections and their treatment, not including the latest treatments. Readers can obtain a copy by writing: Dr. Donohue -- No 503, Box 536475, Orlando, FL 32853-6475. Enclose a check or money order (no cash) for $4.75 U.S./$6 Can. with the recipient's printed name and address. Please allow four weeks for delivery.

Fatty Liver

Obesity and diabetes epidemics spur increase in nonalcoholic steatohepatitis
Liver transplantations for NASH-cirrhosis grew more than 600 percent over past decade

Nonalcoholic steatohepatitis (NASH) occurs when fat builds up in the liver. This accumulation of fat damages the liver and leads to cirrhosis. NASH is rapidly increasing in the U.S. mainly related to the epidemics of obesity and diabetes. As a result, the proportion of liver transplantations performed for NASH cirrhosis rose dramatically from roughly 1% in 1997-2003 to more than 7% in 2010. However, according to new research published in Liver Transplantation, a peer-reviewed journal of the American Association for the Study of Liver Diseases, post-transplantation survival for NASH patients is excellent, with one-year survival rates near 88%.

Excessive fat in liver cells in the absence of alcohol is known as non-alcoholic fatty liver disease (NAFLD) and is the most common liver disease in the U.S., affecting nearly 30% of the general population experts say. Previous research found that 15% to 20% of those with NAFLD have NASH—the most severe form of fatty liver causing inflammation and fibrosis. Primary risk factors for both NAFLD and NASH are central obesity, insulin resistance, and diabetes, all of which are increasingly prevalent and could impact the future demand for liver transplantation. In fact, prior studies suggest that by 2025 more than 25 million Americans may have NASH, which may progress to cirrhosis, liver cancer, and liver failure in 20% of these cases. This influx of new cases has the potential to dramatically worsen the shortage of organs available for transplantation.

In the current study, Dr. Anita Afzali and colleagues from the University of Washington in Seattle investigate the proportion of liver transplantations of NASH-related cirrhosis in the U.S. and estimate survival rates of those patients following transplantation. "With the epidemics of obesity and diabetes giving rise to cases of NAFLD and NASH, it is important to understand the impact of these metabolic conditions on the outcomes after liver transplantation," says Dr. Afzali.

The researchers used data collected by the United Network for Organ Sharing (UNOS) for all liver transplants performed in the U.S. from January 1, 1997 to October 31, 2010. A total of 53,738 transplant patients 18 years of age or older were included in the analysis. The team collected data on primary diagnosis for all study patients, categorizing those as NASH, cryptogenic cirrhosis, hepatitis C virus (HCV), alcohol-related cirrhosis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, autoimmune hepatitis, acute hepatic necrosis, and hepatocellular carcinoma (HCC).

The research found that only 279 transplantations for NASH-cirrhosis (1.2%) were performed between 1997 and 2003, but increased dramatically to 1,531 (7.4%) between 2004 and 2010. The team found that by the end of the study period NASH was the fourth most common indication for transplantation behind HCC (34%), HCV (22%), and alcohol-related liver disease (11%). Survival was excellent among patients with NASH with 88% surviving at one year, 82% at three years, and 77% at five years following liver transplantation.

Patients with NASH had higher survival rates than patients with HCC, HCV, alcoholic liver disease, acute hepatic necrosis, hemochromatosis and cryptogenic liver disease, but were lower than those with PBC, PSC, autoimmune hepatitis and HBV. Post-transplantation survival was similar in NASH patients compared to non-NASH patients, despite being older, more obese, and more likely to have diabetes. Their analysis shows deaths caused by recurrent disease occurred in roughly 9% of NASH patients compared to 17% of patients without NASH. The authors believe this is likely due to a greater frequency of recurrence of diseases such as HCV in those without NASH.

"Our study confirms post-transplantation survival in recipients transplanted for NASH is excellent and comparable to patients with other liver diseases," concludes Dr. Afzali. "With the shortage of available donor organs, appropriate allocation of livers is an important concern for transplant centers and our findings indicate NASH-cirrhosis patients are potentially good candidates for liver transplantation. However, careful screening for cardiovascular disease prior to transplantation and monitoring of underlying cardiac and metabolic conditions following transplantation is recommended to ensure optimal survival for patients with NASH."


This study is published in Liver Transplantation. Media wishing to receive a PDF of the article may contact

Full citation: "Excellent Post-Transplantation Survival in Patients with Non-Alcoholic Steatohepatitis in the United States." Anita Afzali, Kristin Berry, George N. Ioannou. Liver Transplantation; (DOI: 10.1002/lt.22435) Print Issue Date: January 2012.

Author Contact:To arrange an interview with Dr. Afzali, please contact Carrie Silverman with the University of Washington at or at 206-235-3223.

About the Journal

Liver Transplantation is published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society . Since the first application of liver transplantation in a clinical situation was reported more than twenty years ago, there has been a great deal of growth in this field and more is anticipated. As an official publication of the AALSD and the ILTS, Liver Transplantation delivers current, peer-reviewed articles on surgical techniques, clinical investigations and drug research — the information necessary to keep abreast of this evolving specialty. For more information, please visit Liver Transplantation.

About Wiley-Blackwell

Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit or our new online platform, Wiley Online Library (, one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

Big Pharma


Pharma Closed How Many US Plants This Year?

If you guessed that 38 plants are being closed by drugmakers and biotechs this year, you would be right. Given the extent to which the pharmaceutical industry is downsizing, this most likely would not come as a surprise. But while that certainly is a large number, there were 65 facilities closed in 2010, according to Industrial Info Resources, a research firm that tracks construction projects.

The Best Biotech CEO of 2011 Is ...

TheStreet's biotechnology readers have spoken, and Emmens, who oversaw the successful approval and launch of the hepatitis C drug Incivek and the submission of a groundbreaking cystic fibrosis drug for FDA approval garnered 33% of the vote in the Best Biotech CEO of 2011 poll.

For Your Reading Pleasure

Grand Rounds is a weekly summary of the best health blog posts on the Internet. Each week a different blogger takes turns hosting Grand Rounds, and summarizing the best submissions for the week.

Hosted this week by GlassHospital

Welcome to Grand Rounds, where writers, readers, and bloggers send in their best stuff on a weekly basis to share, cross-pollinate, and build new audiences.

Tip of the hat to Grand Rounds co-creator Nick Genes, MD, PhD, an ER doc in NYC who knows a thing or two about blogging, tweeting and now Tumblr.

The theme of this week’s Grand Rounds is “Finding Meaning in Medicine,” with full attribution to Dr. Rachel Naomi Remen, author of the masterful book Kitchen Table Wisdom: Stories that Heal. My wife and I had the privilege of meeting Dr. Remen in 2008, learning from her during a glorious week in Bolinas, California at the Institute for the Study of Health and Illness.

Dr. Remen is an expert at re-connecting health professionals with what brought us into medicine in the first place. I can think of no better Grand Rounds topic than asking bloggers to share their meaningful stories.

A few submissions

Starting off, I’m linking to a story from Zocalo Public Square by Ken Murray, a family doctor at USC. His piece titled “How Doctors Die” has gone viral, as evidenced by the fact that I’ve seen it linked, sent, and tweeted more than a dozen times in different media.

-Medaholic, a medical student from Canada with an eponymous blog, posted about the time his grandfather was hospitalized and the formative emotional impact that it had on his medical education.

Read more blog posts Here

Source Medscape - Celebrity Diagnosis

By: Gary Schwitzer

What Prevention Magazine Considers a Breakthrough

Some months I can’t wait for my new issue of Prevention magazine to arrive, just so I can see how they’ve stretched the envelope this time.

How about this month’s cover, trumpeting a Cancer Vaccine Breakthrough in big yellow font at lower left of the cover?

Read Entire Blog Post Here


The myth of physician omniscience
How is a doctor allowed to mess around with body parts he doesn't understand?If doctors were required to understand everything we touched we wouldn’t be able to touch you at all!The human body is still a deep mystery. Doctors understand more than most people, but what we know is still a vague approximation. Just because our educated guesses often work out well doesn’t mean we have any idea what’s actually ...

Off The Cuff

Source-New England Journal Of Medicine


Learning about the Safety of Drugs — A Half-Century of Evolution

Jerry Avorn, M.D.

N Engl J Med 2011; 365:2151-2153 December 8, 2011

Interview with Jerry Avorn on the evolving approach to drug safety in the United States. (15:13)

The end of 2011 marks the 50th anniversary of a constellation of events that transformed the way we think about drug safety. A half-century ago, the Food and Drug Administration (FDA) did not have authority to require a manufacturer to meet meaningful efficacy standards or demonstrate that a new product had a reasonable benefit–risk relationship; such determinations were seen as best left to the discretion of physicians. In 1961, Senator Estes Kefauver (D-TN) introduced legislation that would, among other things, give the FDA authority to compel companies to provide efficacy and safety data before a product could be sold. Kefauver was accused of trying to unnecessarily expand the power of government, threatening the viability of the pharmaceutical industry, and inserting Washington bureaucrats between patients and their doctors, limiting the freedom of both. His legislation seemed doomed.

During this period, Frances Kelsey, a new medical review officer at the FDA, was working on her first assignment: approving a sleeping aid called Kevadon. It was widely used in Europe, and the company seeking a U.S. license expected quick approval by an agency that rarely said no to anything. But Kelsey noted that the manufacturer's animal safety data were scanty and inconclusive, the clinical evidence was superficial, and there was no assessment of long-term risk. Its studies of the drug's use in pregnancy were grossly inadequate, despite its promotion for morning sickness. She was also concerned about a recent article in the British Medical Journal associating the drug with persistent neuropathic symptoms. Kelsey told the manufacturer in mid-1961 that in her judgment, there was not enough evidence to warrant approving Kevadon for U.S. use.

Meanwhile, a strange epidemic was unfolding in Europe. Babies were being born in unprecedented numbers with severe limb-reduction defects, their hands or feet emerging directly from their torsos. Once rare, these anomalies were suddenly occurring much more frequently. In the absence of any systematic way to link birth defects with prenatal exposures, causal theories abounded, much as they had a century earlier when cholera swept the continent. Some thought the abnormalities were caused by impure water or nuclear testing or an unknown toxin. Since most cases occurred in West Germany but there were virtually none in East Germany, some questioned whether this was the effect of a surreptitious chemical warfare program originating in the Soviet bloc.1

The answer was eventually uncovered by two astute clinicians, working independently half a world apart. Widukind Lenz, a pediatrician in Hamburg, came across a striking number of such deformed children whose mothers had been prescribed a new sedative, Contergan, during pregnancy. (The drug had been aggressively marketed by its manufacturer as a safe sleeping pill — and also for the treatment of morning sickness, influenza, depression, premature ejaculation, tuberculosis, premenstrual symptoms, menopause, stress headaches, alcoholism, anxiety, and emotional instability, among other uses.) In a do-it-yourself case–control study reminiscent of John Snow's 19th-century analysis of the cholera cases clustering around a particular water pump in London, Lenz identified 46 women who had had babies with a limb-reduction deformity and 300 who had borne normal children. A detailed history of each revealed that 41 of the 46 women with deformed babies had taken Contergan, whereas none in the other group had taken the drug in the fourth to ninth weeks of gestation. In November 1961, Lenz contacted Contergan's manufacturer and asked that the drug be taken off the market; the company refused, saying that the risk was unproven. Two days later, Lenz presented his findings at a pediatric conference in Düsseldorf.2

The same year, in Australia, an obstetrician named William McBride noted a surprising increase in limb-reduction deformities in his maternity hospital. He observed that the mothers of several such babies had taken a drug called Distaval during pregnancy. By November, his findings reached the home office of the British company that sold Distaval — coincidentally, a few days after Lenz made his presentation in Düsseldorf. McBride summarized his findings in a report that appeared in the Lancet on December 16, 1961.3

By the end of that year, as more cases emerged, the details of this pivotal drug-safety catastrophe had come into focus. Contergan was withdrawn from the German market, and Distaval was no longer sold in Australia. However, because the drug was marketed under many different trade names for different indications in various countries, and because international collaborations in pharmacovigilance were not yet in place, the compound continued to be sold elsewhere: as Softenon and Noctosediv in several European countries, as Valgis in Africa, and as Isomin, Glutanon, and 8 other proprietary names in Japan. In all, more than 60 different trade names were used to market the same compound — thalidomide. But by the end of 1961 the drug had been withdrawn in most countries. During its years on the market, it is believed to have caused limb-reduction defects in more than 10,000 children worldwide

Because of the vigilance of the FDA's Kelsey, the Kevadon brand of thalidomide was never sold in the United States. Americans were largely spared the birth defects that afflicted so many families in other countries, except for women who obtained the drug while traveling abroad; 20,000 others were enrolled by their doctors in company-sponsored “seeding studies” designed by the drug's manufacturer to start bringing it to the U.S. market before its expected FDA approval.

Much has changed since the climax of the thalidomide story 50 years ago. The drug became a foundational example for the development of drug-safety policy, legitimizing the idea that governments have the right to require manufacturers to provide adequate data about risk and benefit before they can market a prescription drug. It helped to propel the Kefauver-sponsored legislation from likely failure to the law of the land, setting the stage for new authority for the FDA for decades to come.4 The primitive but effective case-series methods of Lenz and McBride have evolved into much more sophisticated methods for detecting drug risk in populations. Today, large data sets covering tens of millions of patients can be subjected to computer-assisted surveillance in near real-time to assess relationships between medication exposures and clinical outcomes. Although these methods have been practical since the 1980s, the FDA is only now starting to apply them systematically, owing to legislation enacted in 2007 in the wake of the most well-known drug-safety crisis of our own era, that of Vioxx (rofecoxib).

Although thalidomide as a sedative or morning-sickness treatment would never pass any contemporary screen for drug safety, modern pharmacoepidemiology and therapeutics are moving toward managing the fact that useful drugs can cause adverse effects in certain circumstances. Fifty years later, our goals have become more nuanced. We are learning how best to use modern methods of evaluation and surveillance to identify as early as possible drugs that pose unacceptable risk and to constrain or prevent their use. Yet debate continues on whether and how the federal government should restrict the use of medications with unacceptable risks. Since all active compounds have some potential for harm, we are trying to learn how best to regulate, prescribe, and monitor the use of medications in ways that maximize their benefit while reducing the likelihood and severity of adverse effects. The concept of Risk Evaluation and Mitigation Strategies, also mandated in the 2007 legislation, is an attempt to move therapeutics in this direction.5 We still have much to learn about implementing this approach, especially for therapies for new indications that have impressive efficacy as well as substantial risk of toxic effects. One current example is an immunomodulatory agent that has shown great promise for treating both leprosy and multiple myeloma — thalidomide.

Disclosure forms provided by the author are available with the full text of this article at

An audio interview with Dr. Avorn is available at

From Harvard Medical School and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital — both in Boston.

Healthy You


Microbial contamination found in orange juice squeezed in bars and restaurants

Scientists from the University of Valencia in Spain have analysed fresh orange juice squeezed by machines in catering establishments. They have confirmed that 43% of samples exceeded the acceptable enterobacteriaceae levels laid down by legislation. The researchers recommend that oranges are handled correctly, that juicers are washed properly and that the orange juice is served immediately rather than being stored in metal jugs.

Around 40% of the fresh orange juice consumed in Spain is squeezed in bars and restaurants. According to a study conducted by researchers at the University of Valencia (UV) though, poor handling of the oranges and insufficient cleaning of the juicer equipment stimulates bacterial contamination.

The team collected 190 batches of squeezed orange juice from different catering locations and analysed their microbiological content on the same day. The results reveal that 43% of the samples exceeded the enterobacteriaceae levels deemed acceptable by food regulations in Spain and Europe. Furthermore, 12% of samples exceeded mesophilic aerobic microorganism levels.

According to the data published in the Food Control Journal, the presence of Staphylococcus aureus and the Salmonella species was found in 1% and 0.5% of samples respectively.

Isabel Sospedra, one of the authors of the study warns that "generally a percentage of oranges juice is consumed immediately after squeezing but, as in many cases, it is kept unprotected in stainless steel jugs."

In fact, the scientists have found that some juices that were kept in metal jugs presented "unacceptable" levels of enterobacteriaceae in 81% of cases and in 13% of cases with regards to mesophilic aerobic bacteria. However, when the freshly squeezed juice is served in a glass, these percentages fall to 22% and 2% respectively.

As the researcher adds, "it must also be borne in mind that juicers and juicing machines have a large surface area and lots of holes and cavities. This promotes microbial contamination, which is picked up by the juice as it is being prepared."

The conclusion is clear. To ensure consumer health, the experts recommend that juicers are cleaned and disinfected properly. The same goes for the jugs in which the juice is stored although its consumption is better as and when it is squeezed.

Orange juice consumption is common in the catering industry due to its taste and nutritional value. This drink is known for its high content of vitamin C, carotenoids, phenolic compounds and other antioxidant substances.

In 2009, Spaniards drank 138 million litres of orange juice (according to data provided by the Spanish Ministry of the Environment and Rural and Marine Affairs), 40% of which was freshly squeezed and consumed in catering establishments.

I. Sospedra, J. Rubert, J.M. Soriano, J. Mañes. "Incidence of microorganisms from fresh orange juice processed by squeezing machines". Food Control 23 (1): 282-285, 2012 (ya disponible on line).


Some depressed people do worse on drugs: study

Reuters - Up to a fifth of patients being treated for depression with some medications may do worse than those given a placebo, according to a U.S. study.

The findings, published in Archives of General Psychiatry, highlight the importance of quickly identifying how patients respond to certain drugs, said lead author Ralitza Gueorguieva, at the Yale University School of Health.

"Identifying variables that are associated with response is a very important question that we haven't quite tackled," she said.

The researchers combined data from seven studies that randomly assigned patients to receive Eli Lilly's drug Cymbalta, known generically as duloxetine, other antidepressants, or a drug-free pill for two months. The trials involved about 2,500 people with major depression.

People getting the placebo tended to report small, gradual improvements in depression symptoms. But those on Cymbalta or another antidepressant fell into one of two categories: most had steeper, steady improvement in depression symptoms, but a sizeable chunk didn't seem to get any better.

One of the study's authors is an employee of Eli Lilly and another is on the company's scientific advisory board.

Researchers found that patients' symptoms over the first few months of antidepressant use separated them into "responders," who got progressively better, and "non-responders," who didn't improve with treatment but may still have suffered side effects.

About four in five patients on all antidepressants were responders. For Cymbalta, about 84 percent of patients improved but 16 percent did not.

Medication responders saw significantly bigger improvements in their depression symptoms than patients assigned to the placebo. Non-responders, however, actually did worse.

"You know within the first couple weeks of starting a treatment who's the most likely to benefit because they're already starting to show improvement," said Michael Thase, a psychiatrist from the University of Pennsylvania Perelman School of Medicine, who wasn't involved in the study.

"I think this finding holds true for the antidepressants that are most commonly used today," he added, referring to the gap between responders and non-responders.

The side-effects of antidepressants, such as stomach problems and poor sleep, could explain the worse symptoms seen in non-responders compared to placebo patients, he said.

Another expert said the latest research has been trying to identify certain patient characteristics -- for instance, genetics or specific depression and anxiety symptoms -- that could help determine the effectiveness of specific drugs.

"If you can identify people who would be potential responders to a particular medication ... it would be a great, huge advantage for the field," said C. Hendricks Brown, who has studied depression treatments at the University of Miami Miller School of Medicine, but didn't take part in the study. SOURCE:

(Reporting from New York by Genevra Pittman at Reuters Health; editing by Elaine Lies)

Source-UC Berkeley Wellness Letter
January 2012

New Questions About PSA Tests

When the U.S. Preventive Services Task Force recommended in October that men not get routine PSA screening for prostate cancer, many men were surprised and/or angry—similar to the way women felt two years ago when new mammogram guidelines were released. PSA stands for prostate specific antigen, a protein produced by prostate cells and released into the blood.

Even though the PSA blood test can detect cancer early, it saves few, if any, lives and often leads to treatments causing serious complications, according to the draft guidelines from the Task Force. It concluded that the substantial risks of screening outweigh the benefits, which are small at most, and thus the PSA test should be discouraged. (Note: The guidelines focus only on routine screening, not the use of PSA in men with symptoms or signs of prostate cancer or for its use to monitor cancer treatment. Also, the financial costs of testing and treatment were not considerations in the analysis.)

For most American men who have had PSA tests—and especially the 2 million who have been told they have cancer based on results of screening and subsequent biopsies—this was probably a shock. But actually it wasn’t something out of the blue. Three years ago, the Task Force advised against routine PSA tests for men over 75 for the same reasons and, reportedly, it was ready to recommend against routine screening for all men, period. But fears of a backlash (from patients, urologists and politicians) led it to call for more analysis of the data and to postpone the release of the new guidelines.

The value of PSA screening has actually always been questioned. The Task Force has never recommended it, though until now it just said there was insufficient evidence to recommend for or against it for men age 50 to 75. In 2010 the American Cancer Society stopped advising routine screening and urged more caution; it now simply tells men to talk to their doctors about it. Urological and prostate cancer advocacy groups, which have been boosters of screening, are most vocal in disagreeing with the Task Force’s new recommendations.

How can a simple early-detection test for cancer not automatically be a great thing?


The prostate, a gland between the bladder and rectum in men, produces seminal fluid. Cancer of the prostate is the second most commonly diagnosed cancer in men (after skin cancer) and the second leading cause of cancer deaths in men (after lung cancer).

The unusual thing about prostate cancer is that the great majority of tumors—especially in older men—remain small, develop very slowly or not at all, do not spread and cause no symptoms. It’s estimated that 1 in 6 American men will be diagnosed with prostate cancer, and 1 in 36 will die from it—meaning that it is fatal in about 15 percent of diagnosed cases. Thus, far more men die with prostate cancer than from it. In fact, autopsy studies reveal that one-third of men in their forties and fifties and three-quarters of those over 85 had prostate cancer—usually small and harmless—and never knew they had it (they died from something else).

Age greatly increases the risk of prostate cancer—about 85 percent of cases are diagnosed in men over 60, and 70 percent of deaths occur after age 75. Having a brother or father with prostate cancer more than doubles the risk. Black men are 60 percent more likely to develop it than whites, and twice as likely to die from it. Nevertheless, the Task Force did not recommend screening for black men or those with a family history, for lack of evidence of benefit.

The PSA test merely measures the level of this protein in the blood, not cancer. PSA levels rise as a result of prostate disorders—such as infection, benign enlargement or cancer—or sometimes for no apparent reason. The test, which is easy to do and inexpensive, was introduced in the 1980s to monitor men already diagnosed with prostate cancer. But doctors soon began using it to screen healthy men.

The downsides

Unfortunately, PSA is not a very good screening test. The only way to determine which men have cancer is with a biopsy. Only about 20 to 30 percent of men with elevated PSA turn out to have cancer. (There is debate about what cutoff points should be used to define “elevated” and “normal” PSA.) Moreover, a similar percentage of men with PSA levels in the “safe” range do have cancer.

Though experts have proposed ways to improve the interpretation of PSA results—such as assessing PSA level in relation to prostate size and monitoring PSA changes over time—there is still no way to predict with any certainty which low-grade cancers will become aggressive and spread and which will cause no problems.

The biopsies can cause anxiety, pain and, more rarely, infection. But the biggest concern is that abnormal biopsy results usually lead to the treatment of small, slow-growing cancers that would never have become life-threatening—treatment that often has serious adverse effects. (The Gleason score is used to grade the aggressiveness of cancer cells, but more research is needed to determine how much its use reduces mortality rates and overtreatment.) Surgery to remove the prostate and radiation are standard; both treatments often produce erectile dysfunction, urinary problems, incontinence and/or other complications.

Another problem: Choosing a treatment is often confusing, since there is no one “best” option. For older men, “watchful waiting” (or “active surveillance”) rather than treatment is often advised. Studies comparing watchful waiting to surgery or radiation therapy have yielded conflicting results.

Why the drop in death rates?

The good news is that death rates from prostate cancer have been declining since 1990. Some researchers attribute the improvement to PSA testing, though this is debated, since better treatments may deserve most of the credit. But if PSA screening is largely responsible, it’s surprising that studies have been unable to resolve the debate about it.

Even data suggesting that screening saves lives present a sobering picture. According to some estimates, for every man whose life is prolonged because of PSA screening, somewhere between 30 and 100 men end up being treated for a cancer that was never going to harm them. One-third to one-half of those treated will have adverse effects like erectile dysfunction and urinary incontinence. And about 1 in 200 men die from complications of prostate surgery. Many men with faster-growing prostate cancer will die from it even if PSA screening detects it early and they are treated for it.

What to do

We do not recommend routine PSA screening—that is, all men should not be automatically tested. The decision is a personal one, and men should discuss the pros and cons of PSA testing with their doctors starting at about age 50, earlier if they are at high risk. Keep in mind, if you decide to be screened, no one knows what screening intervals or PSA thresholds are optimal. Even if you are screened periodically, you should stop at age 75, since further testing is very unlikely to prolong lives.

Studies have shown that when the pros and cons of PSA testing are fully described to men who have not yet made up their minds, they are more likely to decide against it. Such patient/doctor discussions will undoubtedly affect a man’s decision about screening far more than advice from the Task Force.

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