Thursday, January 31, 2013

Target 'super-spreaders' to stop hepatitis C

Target 'super-spreaders' to stop hepatitis C

Each intravenous drug user contracting Hepatitis C is likely to infect around 20 other people with the virus, half of these transmissions occurring in the first two years after the user is first infected, a new study estimates.

The work, led by researchers from Oxford University, suggests that early diagnosis and treatment of Hepatitis C in intravenous drug users could prevent many transmissions by limiting the impact of these 'super-spreaders' (a highly infectious person who spreads a disease to many other people).

Working out 'who has infected who' in fast-spreading diseases such as influenza is often relatively straightforward, but in slow-spreading diseases such as Hepatitis C and HIV, where instances of transmission are spread over months or years, it is extremely difficult. The new approach, developed by a team from Oxford University, University of Athens and Imperial College, combines epidemiological surveillance and molecular data to describe in detail, for the first time, how Hepatitis C spreads in a population.

A report of the research appears in this week's PLOS Computational Biology.

'For the first time we show that super-spreading in Hepatitis C is led by intravenous drug users early in their infection,' said Dr Gkikas Magiorkinis of Oxford University's Department of Zoology, lead author of the study. 'Using this information we can hopefully soon make a solid argument to support the scaling-up of early diagnosis and antiviral treatment in drug users. Helping these people and stopping the spread of Hepatitis C is our ultimate target.'

The World Health Organisation has identified Hepatitis C as a major public health problem: up to 180 million people worldwide live with the virus, most are unaware that they have been infected and remain undiagnosed for more than 10 years. 20% of those infected will develop cancer or liver scarring (cirrhosis) after 20 years of infection, at which point the only treatment is liver transplantation, which costs around £100,000 ($160,000) for each patient.

Unlike other forms of Hepatitis there is currently no vaccine available for Hepatitis C, although there are effective treatments. The virus mainly transmits through contaminated blood and before 1990 the major transmission route was blood transfusions and blood products. Since screening for blood transfusions was introduced, after the discovery of the virus in 1989, the only significant transmission route for Hepatitis C is now intravenous drug use – users are at risk through the sharing and re-use of syringes.

'Working out how many people are likely to be infected by each 'super-spreader' of Hepatitis C, as well as how soon they will be infected, has been a puzzle for over 20 years,' said Dr Magiorkinis. 'Our research has resolved this issue and paves the way for a modelling study to show what kind of public health interventions could really make a difference. Our approach should also be very useful to those studying HIV.'

The research draws on data from four Hepatitis C epidemics in Greece, using information on 943 patients in treatment studies between 1995 and 2000, and around 100 genetic sequences representative of the epidemic taken from frozen plasma samples collected between 1996 and 2006. The team then used a mathematical model to estimate the variance of secondary infection and how long it takes for such infection to occur.

Interferon free regimens for the “difficult to treat”: are we there?


Interferon free regimens for the “difficult to treat”: are we there?  

Maria-Carlota Londoño, Sabela Lens, Xavier Forns PII: S0168-8278(13)00021-4

Reference: JHEPAT 4556 To appear in: Journal of Hepatology

Received Date: 11 December 2012 Revised Date: 7 January 2013 Accepted Date: 8 January 2013

(In Press Accepted Manuscript)     

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Developments in the treatment of chronic hepatitis C over the last 2 years have been remarkable. For the first time ever, we are now certain that this chronic infection can be cured without the need of interferon and ribavirin. Gane and colleagues provided the proof of concept that oral antiviral therapy with two direct-acting antivirals (DAAs) without interferon can suppress viral replication (1). In their study, they showed that the combination of a NS5B nucleoside polymerase inhibitor (RG7128) and a NS3 protease inhibitor (danoprevir) had potent antiviral activity even in null-responders; some patients achieved undetectable HCV-RNA only 14 days after treatment initiation. Unfortunately, the combination of DAAs in this study was limited to 2 weeks and was followed immediately by treatment with peginterferon and ribavirin, thus preventing the assessment of sustained virological response to an interferon-free regimen (1). The combination of the protease inhibitor asunaprevir with the NS5A inhibitor daclatasvir is the first oral interferon-free regimen proved to be effective (2, 3). In the study by Lok et al (2), 11 previous null responders received both drugs for 24 weeks and a total of 4 patients (2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) achieved a sustained virologic response (SVR).

In the study by Chayama et al (3) 11 genotype 1b null responders underwent the same interferon-free regimen and the 9 individuals who completed 24 weeks of therapy achieved SVR. In this issue of Journal of Hepatology, Suzuki et al (4) evaluated the efficacy of dual therapy with asunaprevir and daclatasvir in 43 subjects infected with genotype 1b considered poor candidates for current treatment for hepatitis C (21 null-responders and 22 ineligible or intolerant to interferon-based therapy). SVR at 12 and 24 weeks was 90% for null-responders and 64% for ineligible/intolerant to interferon-based therapies.

Treatment was well tolerated and virological failures were only observed in the cohort of ineligible/intolerant patients (3 breakthroughs and 4 relapses). In the accompanying manuscript, Karino et al (5) characterized the escape viral mutations in patients experiencing virological failures. The authors found that NS3 and NS5 resistance-associated variants (RAVs) were detected together at the time of virological failures.

One of the strengths of the study of Suzuki et al (4) is that it deals with difficult to treat patients: well documented null responders and patients who are intolerant or ineligible to interferon. Although the latter group was rather heterogeneous (individuals older than 70 years, with depression or other comorbidities), this profile of patients represents a significant proportion of our current candidates to antiviral therapy. Obviously, the combination of peginterferon, ribavirin and a first generation protease inhibitor (boceprevir or telaprevir) is not an option for patients with absolute contraindications to interferon and it is also a poor choice for individuals with comorbidities or those who are old. In Japan and China, hepatitis C virus expanded decades before that of the United States and Europe (6). Therefore, candidates to antiviral therapy in Asia are often older than corresponding patients in Western countries. Older age is not an absolute contraindication for an interferon-based therapy. A French group showed good efficacy in a small group of patients older than 65 years treated with pegylated interferon and rivabirin (7). Nevertheless, other studies have demonstrated a trend towards lower SVR rates, as well as higher rates of dose reductions and discontinuations of therapy in this population as compared to younger individuals (6, 8). Currently, there are no data on the safety and efficacy of triple therapy in old patients. In the CUPIC French cohort, cirrhotic patients up to 83 years old have been included: though the number of severe adverse events using triple therapy seems clearly higher than those reported with peginterferon and ribavirin alone (9), a specific analysis in older patients has not been performed.

Similarly, triple therapy is not an ideal alternative for most previous null responders, since SVR rates in this subpopulation ranks only between 30% to 40% (10, 11). Moreover, subgroup analyses from the REALIZE study (10) suggests that in cirrhotic null responders SVR is below 15%. In order to accomplish the definition of “difficult to treat” patients it would have been interesting if the study by Suzuki et al. had included patients with advanced liver disease (biopsy-proven cirrhosis was an exclusion criteria).

Response rates obtained in this study using daclatasvir and asunaprevir can be considered excellent. It is surprising though, that the only the virological failures reported were in the group of intolerant/ineligible patients (5). Although the small number of patients precludes any definitive interpretation, there are several potential explanations. Firstly, it is important to notice that 10 out of the 21 null responders (sentinel cohort) received a significantly higher dose of asunaprevir, which was not the case in any of the 22 intolerant/ineligible individuals. Second, patients experiencing virological failure had below-median daclatasvir and asunarpevir levels, but this was also the case for other individuals who achieved sustained viral clearance. A lack of compliance did not seem to play a major role in the lower efficacy in this group (though cannot be completely excluded). A more interesting hypothesis is the potential effect of pre-existing resistance-associated variants (RAVs). In a complementary manuscript Karino et al. (5) performed a careful characterization of virological escape mutants in patients included in the first study. Interestingly, most patients experiencing viral breakthrough or relapse had daclatasvir RAVs at baseline, being NS5A-Y93H the predominant polymorphism in all 3 patients with virological breakthrough and in 2 of the 4 relapsers. The global prevalence of this variant is around 4% (5, 12) and may be higher in genotype 1b-infected patients (~ 10%). Indeed, NS5A-Y93H was found at baseline in five other patients who achieved SVR in this study.

In every patient with virological failure resistant variants to both agents emerged together at the time of failure (NS3-D168A/V and NS5A-L31M/V-Y93H). At baseline, a combination of these NS3 and NS5A variants was not detected by clonal sequencing; however their presence at low levels cannot be excluded due to the limited number of clones analyzed. Currently, assessment of minor NS3 plus NS5A RAVs from the same RNA sequence is not possible by ultradeep sequencing technologies, since the size of the analyzed fragments is still a limitation (a fragment of ~ 4000 base pairs encompassing NS3, NS4 and NS5A is fair too large for the current technology).

A final point analyzed in the accompanying manuscript by Karino et al was the persistence of RAVs after treatment interruption (5). This is a very relevant topic, since it may impact future treatment options in patients who develop drug resistance. As reported with other protease inhibitors, asunaprevir-resistant NS3-D168 substitutions generally decayed during the follow-up period, which implies a lack of replicative fitness compared to the wild-type virus in the absence of selective pressure (drug). This was also reproduced in the replicon system, where double NS3 RAVs (D168V plus Q80L or S122G) had a replicative ability similar to the D168V variant alone. Obviously, a more thorough sequence analysis using ultra-deep pyrosequencing would be necessary to fully establish the dynamic decay of these RAVs after treatment interruption and to make sure that these variants do not remain enriched for longer periods relative to baseline. In fact, a small study including 5 patients who were first treated with simeprevir monotherapy (5 days) and then retreated more than 1 year later with pegylated interferon, ribavirin and simepervir analyzed the potential clinical implications of the presence of RAVs. In this study (13) 3 patients achieved SVR and 2 did not. Deep sequencing indicated low-level persistence of simeprevir RAVs in the 2 patients who did not achieve SVR. We do not know if the presence of these resistant strains at low levels explained the lack of response to re-treatment. What is really interesting in the study by Karino et al (5) is that in some individuals, NS5A variants associated with daclatavir resistance persisted for at least 48 weeks after treatment interruption. As already mentioned, longer follow-up studies are important to establish the clinical impact of these more fitted resistant strains in case these patients will be retreated with NS5A inhibitors.

Overall, the ideal combination of DAAs is still unknown, but some of the inherent characteristics of the antiviral agents may help to predict which combination will be more effective (Table 1). The inclusion of a nucleo(s)tide NS5B polymerase inhibitor in a combination seems reasonable (14). These drugs offer a high barrier to resistance (RAVs have a very poor fitness), are pangenotypic and have proved to be very effective in several phase 2 trials. The simple combination of sofosbuvir and ribavirin for 12 weeks appears to be extremely successful in naïve genotype 1, 2 or 3 patients (though this combination using such a short regimen is insufficient to cure previous null responders) (15). Combinations including more than 2 DAAs targeting different viral proteins also seem a good approach. Recently, a study including both naïve and null responder genotype 1 patients assessed the efficacy of ABT450/r (ritonavir-boosted NS3 inhibitor), ABT267 (NS5B non nucleoside inhibitor), ABT 333 (NS5A inhibitor) and ribavirin. This combination SVR12 rates close to 100% in naives and around 90% in null-responders (16). Unfortunately, patients with advanced liver disease have not yet been included in these studies. The only data regarding cirrhotic patients treated with oral regimens comes from the SOUND-C2 study, where a NS3 protease inhibitor (faldaprevir), a non nucleoside NS5B inhibitor (BI207127) and ribavirin were combined in genotype 1 naïve patients: reported SVR12 rates in cirrhotics were around 60%(17).

Within the next few years, we will certainly witness more progress. When choosing a combination of antiviral agents, we will need to take into consideration a certain number of variables: potency, genetic barrier to resistance, range of activity (pangenotypic or not), potential drug-drug interactions. Importantly, safety and simplicity of the regimen will also be very relevant. Up to now, most of the oral compounds appear to be safe and well tolerated by most patients, but until large phase 3 studies are finished, safety needs to be closely monitored. Most of our current knowledge on interferon-free regimes is based on phase 2 trials including small numbers of patients. Added to which, we still have very little information on the safety and efficacy of these regimens in difficult to treat subjects, particularly in null responders with advanced fibrosis or cirrhosis, or in special populations such as transplant patients with hepatitis C recurrence. Over the next 2 to 3 years, we will start to see data on large cohorts (phase 3 studies) and in small series of really difficult to treat individuals and in special populations. By then, it will be easier to answer the question: are we there?

Table 1. Characteristics of direct antiviral agents approved for hepatitis C treatment or entering phase 3 studies.

Click To Enlarge

1. Gane EJ, Roberts SK, Stedman CA, Angus PW, Ritchie B, Elston R, Ipe D, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-
1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet
2. Chayama K, Takahashi S, Toyota J, Karino Y, Ikeda K, Ishikawa H,Watanabe H, et al. Dual therapy with the nonstructural protein 5A inhibitor,daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology
3. Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R,Reindollar R, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012;366:216-224.
4. Suzuki Y, Ikeda K, Suzuki F, Toyota J, Karino Y, Chayama K, Kawakami Y, et al. Dual Oral Therapy with Daclatasvir and Asunaprevir for Patients with HCV Genotype 1b Infection and Limited Treatment Options. J Hepatol 2012.
5. Karino Y, Toyota J, Ikeda K, Suzuki F, Chayama K, Kawakami Y, Ishikawa H, et al. Characterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir. J Hepatol 2012.
6. Iwasaki Y, Ikeda H, Araki Y, Osawa T, Kita K, Ando M, Shimoe T, et al. Limitation of combination therapy of interferon and ribavirin for older patients with chronic hepatitis C. Hepatology 2006;43:54-63.
7. Thabut D, Le Calvez S, Thibault V, Massard J, Munteanu M, Di Martino V, Ratziu V, et al. Hepatitis C in 6,865 patients 65 yr or older: a severe and neglected curable disease? Am J Gastroenterol 2006;101:1260-1267.
8. Hu CC, Lin CL, Kuo YL, Chien CH, Chen SW, Yen CL, Lin CY, et al. Efficacy and safety of ribavirin plus pegylated interferon alfa in geriatric patients with chronic hepatitis C. Aliment Pharmacol Ther 2013;37:81-90.
9. Hezode C, Dorival C, Zoulim F, Larrey D, Pol S, Cacoub P, Canva V, et al. Safety and efficacy of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in 455 cirrhotic non responders. Week 16 analysis of the French early access program (ANRS CO20-CUPIC) in real-life setting. (Abstract). Hepatology 2012;56:217A.
10. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011;364:2417-2428.
11. Vierling JM, Flamm SL, Gordon S, Lawitz E, Bronowicki JP, Davis M, Yoshida EM, et al. Efficacy of Boceprevir en prior null-responders to Peginterferon and Ribavirin: The PROVIDE Study. (Abstract). Hepatology 2011;54:796A.
12. Kuiken C, Yusim K, Boykin L, Richardson R. The Los Alamos hepatitis C sequence database. Bioinformatics 2005;21:379-384.
13. Lenz O, de Bruijne J, Vijgen L, Verbinnen T, Weegink C, Van Marck H, Vandenbroucke I, et al. Efficacy of Re-treatment With TMC435 as Combination Therapy in Hepatitis C Virus-Infected Patients Following TMC435 Monotherapy. Gastroenterology 2012;143:1176-1178 e1176.
14. Chung RT. A watershed moment in the treatment of hepatitis C. N Engl J Med 2012;366:273-275.
15. Gane EJ, Stedman CA, Hayland RH, Sorensen RD, Symonds WT, Hindes R, Berrey MM. Once Daily Sofosbuvir (GS-7977) Plus Ribavirin in Patients with HCV Genotypes 1, 2, and 3: The ELECTRON Trial. Hepatology 2012;56:306A.
16. Kowdley K, Lawitz E, Poordad F, Cohen DE, Nelson DR, Zeuzem S, Everson GT, et al. A 12-Week Interferon-free Treatment Regimen with ABT- 450/r, ABT-267, ABT-333 and Ribavirin Achieves SVR12 Rates (Observed Data) of 99% in Treatment-Naïve Patients and 93% in Prior Null Responders with HCV Genotype1 Infection. (LB Abstract). AASLD 2012.
17. Soriano V, Gane EJ, Angus P, Stickel F, Bronowicki JP, Roberts S, Manns MP, et al. Efficacy and safety of the interferon (IFN)-free combination of BI 201335 + BI 207127 ± ribavirin (RBV) in treatment-naïve patients with HCV genotype (GT) 1 infection and compensated liver cirrhosis: Results from the SOUND-C2 study (Abstract). Hepatology 2012;56:234A.

Liver Cancer-Phase III HEAT trial of Thermodox Fails to Meet Goals

Investment Commentary

Celsion Liver Cancer Trial Fails to Meet Goals, Stock Plunges
Catherine Arnst1

In a major setback, Celsion (NASDAQ: CLSN), based in Lawrenceville, NJ, reported today that its lead drug candidate failed in a Phase III clinical trial for treatment of primary liver cancer. CEO Michael Tardugno told an investor conference call this morning that the result “was not even close” to meeting the trial’s goals.

Investor reaction was swift and furious, with Celsion’s share price dropping 80 percent in the first hour of trading, to $1.59 from the previous close of $8.02. Celsion’s stock had more than tripled in price over the prior year.

Celsion said that the Phase III HEAT trial of Thermodox—a proprietary reformulation of the chemo drug doxorubicin—in combination with radiation was designed to slow the cancer from spreading, a measure called progression free survival, by at least 33 percent compared with the control arm, but did not meet that goal. The trial results, Tardugno said, would not justify filing for approval in any country.

Part of the problem, Tardugno said, is that patients in the control arm did about 20 percent better on standard treatment than the company had projected. Cancer trials can sometimes take years to enroll patients and compile results from the time the trial design was approved, and during that time the standard of care continues to improve, making it more difficult for new treatments to show an advantage over existing therapies.

Celsion will continue to study the results to determine whether patients currently on Thermodox would be followed to determine whether the drug can extend overall survival.

The results were released just a week after the company announced a technology development deal for Thermodox in liver cancer with Zhejiang Hisun Pharmaceutical, a major Chinese drug company, that could have been worth up to $100 million over 10 years if the drug had succeeded. Celsion has already received an initial payment of $5 million from Hsuin, which Tardugno said the company is not required to give back the payment in light of the trial failure.

Tardugno sought to reassure investors by telling them the company has approximately $27 million in cash on hand as of today, enough money to fund its operations “well into 2014.”

Celsion’s drug technology, developed in partnership with Duke University, encases chemotherapy drugs in tiny bubbles called liposomes that are then activated by low levels of radiation to deliver their payload directly to cancer cells. Thermodox won fast-track designation from the Food & Drug Administration in August 2010 for development against primary liver cancer.

Celsion also has heat activated liposomes in Phase II clinical trials for breast cancer and a second form of liver cancer, but Tardugno said the company will have to give the latter trial “some consideration” before it decides whether or not to continue in light of the HEAT failure.

Celsion plunges 80 percent as liver cancer therapy fails trial

Jan 31, 2013 11:36am EST
(Reuters) - Celsion Corp shares plunged by more than 80 percent after a late-stage study of the company's experimental liver cancer treatment ThermoDox failed to meet the main goal of increasing patients' survival without worsening their cancer.

The stock fell to a low of $1.41 before recovering slightly to trade at $1.46 on heavy volume on the Nasdaq on Thursday.

"I don't believe the data will support (marketing) registration in any of the major markets," Celsion Chief Executive Michael Tardugno said on a conference call.

The trial, named HEAT, consisted of 701 patients across 11 countries and was designed to show a 33 percent improvement in progression-free survival.

Celsion said it was conducting additional analyses of data from the trial to assess the future value of ThermoDox.

Patients on the control arm performed about 20 percent better than expected whereas those on ThermoDox performed worse than anticipated, Roth Capital Partners analyst Joseph Pantginis said, quoting the company.

"We are disappointed by the failure of the HEAT study and we highlight the increased risk around the company's pipeline which is driven by ThermoDox," he said.

ThermoDox is also being tested in mid-stage studies as a drug-delivery method for breast and colorectal cancers.

Celsion CEO Tardugno said the company will continue enrolling patients in the mid-stage breast cancer study.

ThermoDox utilizes a liposome -- a tiny bubble composed of lipids -- as a vehicle to transport a commonly used chemotherapy drug called doxorubicin, directly to the tumor.
Localized heat releases doxorubicin, depositing it in and around the tumor, maximizing the effect of the medication.

The liver-cancer study compared the HEAT results against patients treated with a procedure where tumors are destroyed using electricity, otherwise called radiofrequency ablation.
Pantginis downgraded Celsion's rating to "neutral" from "buy" and slashed his price target on the stock to $1.70 from $10, saying the target is now based solely on the mid-stage study of ThermoDox in breast cancer.

Celsion said it had sufficient cash to cover its expenses well into 2014. It has unaudited cash and investments of about $27 million.

CEO Tardugno said the company will review its colorectal cancer trial in the context of the HEAT results and then decide on whether to continue with the study.

(Reporting By Pallavi Ail in Bangalore; Editing by Roshni Menon and Sreejiraj Eluvangal)

Wednesday, January 30, 2013

Interferon May Be Harmful in Retreatment of Hepatitis C

Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C

Some patients with chronic hepatitis C progress from a relatively benign condition to a life-threatening illness. Interferon has been used to try to prevent this but researchers have struggled to investigate its effects reliably. Ron Koretz from Granada Hills in the USA, tells us about the January 2013 update of the relevant Cochrane Review, outlining what the authors did to try to solve this and what they found.

Listen below

Download [mp3]

To browse Podcasts by topic, please visit the new Cochrane Summaries beta site here 

Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C Updated
Koretz RL, Pleguezuelo M, Arvaniti V, Barrera Baena P, Ciria R, Gurusamy KS, Davidson BR, Burroughs AK
Published Online:
January 31, 2013
Antiviral treatment for chronic hepatitis C infections is currently judged as being successful if, at least six months after therapy, blood tests for hepatitis C viral RNA are negative; this has been called a sustained viral response. In the past, other outcomes for treatment have included improvements in biochemical tests (especially liver enzyme tests such as the serum alanine aminotransferase) or evidence of reduced inflammation and/or fibrosis on subsequent liver biopsies. All of these outcomes are tests, and it has been assumed that if the test gets better the patient will as well. However, there is no direct evidence that has proven that these outcomes are valid because there have been no long-term trials that have shown that an improvement in these tests translates into reduced mortality or morbidity. Patients who fail to have sustained viral responses after an initial course of therapy do become potential candidates for retreatment; some of them may be intolerant to ribavirin, and possibly even the newer protease inhibitors, so retreatment would have to be with interferon alone. It has also been speculated that long-term treatment (namely treatment for several years) might be beneficial; such long-term therapy would be further complicated if multiple drugs were used because of the additional drug toxicities and costs, so interferon alone could be considered.....
Continue to updated material @  Cochrane Summaries


Chronic hepatitis C: Interferon may be harmful in re-treatment

People with hepatitis C and chronic liver disease who relapsed or failed to respond to initial treatment are unlikely to improve on interferon retreatment. In fact, they may face an increased risk of dying sooner, and are likely to experience a variety of adverse effects, according to an updated systematic review published in The Cochrane Library.

Hepatitis C affects around 170 million people worldwide. In some cases, infection leads to chronic liver disease, liver failure or liver cancer, eventually resulting in death. Treatment is based on antiviral drugs.

Interferon monotherapy, meaning using interferon alone, is not the first choice of therapy for most clinicians, but it is used in some patients when other drugs cannot be used. Despite costing thousands of dollars to treat one patient for a year, there is currently little evidence that it works. Treatment is considered to have been successful if the virus cannot be detected in a patient's blood six months after treatment. This outcome is known as sustained viral response (SVR). However, it has never been confirmed that SVR leads to an improvement in the patient's disease state or their chances of survival.

The authors of the review analysed data from seven trials involving a total of 1,976 patients with chronic hepatitis C liver disease who were being retreated with interferon monotherapy having previously been treated unsuccessfully. When they included all trials in their analysis, the risk of death was no higher for interferon than for placebo or no treatment. However, the researchers also performed a further analysis, leaving out studies that had a high risk of bias and gave less reliable estimates of effect. For example, one of these trials was not blinded, was stopped before the planned number of patients had been enrolled, and did not have all of those who had been enrolled counted in the final analysis. This left the two largest trials, together incorporating 1,676 patients. Focusing only on these trials, the risk of death was significantly higher at 9.4% for interferon retreatment compared to 6.7% for placebo or no treatment.

"It was troubling to see that in those trials providing the most reliable estimates of treatment effects, interferon seemed to increase the risk of death," said lead researcher Ronald Koretz of Granada Hills in California, US. "Based on these results, interferon monotherapy cannot be recommended for chronic hepatitis C patients who have already failed one course of treatment and are being retreated. Furthermore, patients who are receiving interferon as part of a combination therapy should be informed about this potential adverse effect."

Interferon treatment did seem to reduce levels of hepatitis C virus in the blood compared to controls, resulting in what would be considered successful treatment or SVR. However, since this response was not associated with an improvement in disease or risk of death, the review suggests that SVR may be inadequate as an indicator of a successful treatment outcome. "Sustained viral response did not suggest that a patient who was destined to develop symptoms or death from hepatitis C was cured, at least in this setting. This tells us that as a treatment outcome it is not universally reliable and needs to be validated before it can be viewed as the goal of any therapy in other clinical scenarios," said Koretz.

Patients in the treatment group were also more likely to suffer adverse effects. Although the drug did appear to reduce the incidence of nonfatal internal bleeding, the researchers conclude that it is so expensive that it may be hard to justify based on this one small benefit.

Interferon May Be Harmful in Retreatment of Hepatitis C


When patients with hepatitis C and chronic liver disease suffer relapses or fail to respond to initial treatment, monotherapy with interferon may not be a good idea, according to results from a recent meta-analysis. In fact, employing that approach may raise the risks for death and adverse effects.

The review is published in the January issue of the Cochrane Database of Systematic Reviews and was conducted by Ronald Koretz, MD, professor of medicine, digestive diseases and gastroenterology, David Geffen School of Medicine, University of California, Los Angeles, and colleagues.

"The widely-accepted treatment outcome for chronic hepatitis C is the sustained viral response (that is, no measurable viral RNA in blood six months after treatment). However, this surrogate outcome (as well as the previously employed biochemical and histologic ones) has never been validated," the authors write.

The lack of validation is not surprising, the authors say, because very few randomized clinical trials evaluating clinical outcomes (mortality or manifestations of cirrhosis) have been conducted, as patients usually do not die or develop cirrhosis until years after they have been infected.

Patients who undergo initial therapy but do not produce sustained viral responses become potential candidates for retreatment, the authors note, but for some patients in whom standard treatment with ribavirin or protease inhibitors cannot be tolerated, clinicians often consider retreatment with interferon to be a reasonable option.

All-Cause Mortality Worse
To find out more about the actual clinical effects of retreatment with interferon, the investigators reviewed data from 7 clinical trials in which monotherapy retreatment with interferon was compared with placebo or no treatment.

Two of the trials (the Hepatitis C Antiviral Long-term Treatment against Cirrhosis [HALT-C] and Evaluation of Peglntron in Control of Hepatitis C Cirrhosis [EPIC-3] trials) were considered to be at low risk for bias. Together, those trials included 1676 patients. Both assessed the clinical outcomes of patients with severe fibrosis who underwent long-term low-dose retreatment with pegylated interferon therapy.

The other 5 trials included a total of 300 patients and were considered to be at high risk for bias.
Dr. Koretz and colleagues report that when they included all trials with published outcomes in their review they saw no significant difference in all-cause mortality (78/843 [9.3%] vs 62/867 [7.2%]; risk ratio [RR], 1.30; 95% confidence interval [CI], 0.95 - 1.79; 3 trials). They also did not find a significant difference in hepatic-related mortality (41/532 [7.7%] vs 40/552 [7.2%]; RR, 1.07; 95% CI, 0.70 - 1.63; 2 trials).

However, when the reviewers included only the 2 trials considered at low risk for bias, they noted that all-cause mortality was significantly higher among patients who received interferon (78/828 [9.4%] vs 57/848 [6.7%]; RR, 1.41; 95% CI, 1.02 - 1.96).

They do note, however, that there was less variceal bleeding in patients who received interferon (4/843 [0.5%] vs 18/867 [2.1%]; RR, 0.24; 95% CI, 0.09 - 0.67; 3 trials). Still, the researchers comment that the prohibitive cost of interferon would not justify it for this indication alone.
Patients administered interferon were no more likely to develop ascites, encephalopathy, or hepatocellular carcinoma or to need liver transplants.

Only one of the trials included quality-of-life data, and in that trial pain scores were significantly worse in patients receiving interferon, the reviewers write. Patients receiving interferon were also more likely to suffer adverse effects, most commonly hematologic complications, infections, influenza-like symptoms, and rashes.

SVR a Surrogate Marker?
Interferon therapy did appear, however, to be associated with significantly better viral responses (20/557 [3.6%] vs 1/579 [0.2%]; RR, 15.38; 95% CI, 2.93 - 80.71; 4 trials). In addition, METAVIR activity scores, gauging degree of inflammation as well as the extent of fibrosis, also improved (36/55 [65%] vs 20/46 [43.5%]; RR, 1.49; 95% CI, 1.02 - 2.18; 2 trials). However, the reviewers say they saw no significant differences in histologic assessments of fibrosis.

The authors stress that the clinical data they reviewed were limited to patients with histologic evidence of severe fibrosis who were retreated with pegylated interferon.

"In this scenario, retreatment with interferon did not appear to provide significant clinical benefit and, when only the trials at low risk of bias were considered, retreatment for several years may even have increased all-cause mortality. Such treatment also produced adverse events," the authors note.

In conclusion, they write, "Two of the commonly employed surrogate markers, sustained viral response and markers of inflammation, failed to be validated since they improved even though the clinical outcomes did not (or may even have become worse). This failure to validate the sustained viral response in this group of patients with a low sustained viral response rate suggests that the presumed validity of the use of sustained viral responses in other groups of patients with chronic hepatitis C viral infections who receive treatment must be formally validated."

The authors have disclosed no relevant financial relationships.
Cochrane Database Syst Rev. 2013:1:CD003617.


HCC incidence increased in HIV/hepatitis coinfection

HCC incidence increased in HIV/hepatitis coinfection

Merchante N. Clin Infect Dis. 2013;56:143-150.

January 30, 2013

The incidence of hepatocellular carcinoma has increased among patients coinfected with HIV and hepatitis, according to researchers in Spain.

Hepatocellular carcinoma (HCC) is emerging as a new clinical problem in the HIV-infected patient, especially in those also infected with hepatitis C virus,” Nicolás Merchante, MD, of the Hospital Universitario de Valme in Sevilla, Spain, told Infectious Disease News.

“In our country, HCC incidence has dramatically increased by a factor of 14 in 10 years. Late diagnosis is still a problem, and mortality is high. Clinicians need to be aware of this complication of cirrhosis and implement strategies for early diagnosis, which may allow for potentially curative therapy.”

Nicolas Merchante, MDNicolás Merchante

The study included 82 patients with HIV who developed HCC in Spain before Dec. 31, 2010. All patients were coinfected with hepatitis: 66 had HCV, six had hepatitis B virus and 10 had both HBV and HCV. Twenty-two patients with HIV/HCV coinfection had previously received treatment for HCV. Of those, six achieved sustained virologic response for a median of 28 months until HCC diagnosis.

The first case of HCC in a patient with HIV was reported in 1999. Before Dec. 31, 2004, there were only 16 cases of HCC documented among patients with HIV. After this date, there were 66 new cases diagnosed. Until 2003, the incidence density rate of HCC was between 0 and 0.6 cases per 1,000 person-years. In 2008 and 2009, the incidence density rate of HCC was 2.8 cases per 1,000 person-years.

Most cases of HCC were diagnosed at an advanced stage because of symptoms. Only 30% of the patients met criteria for liver transplantation. Among the patients with HCC diagnosis, 33 received treatment: 11 received potentially curative treatment and 22 received noncurative treatment. Most of the patients (79%) died after HCC diagnosis. The median survival was 91 days, and all deaths except for two were related to HCC.

Among patients who received potentially curative therapy, 28% died vs. 87% who did not receive curative therapy. Median survival after HCC diagnosis was lower in those who received no therapy or noncurative therapy.

“The implications of this study for clinical practice are many,” Merchante said. “Routine screening for HCC in HCV/HIV coinfected patients with cirrhosis is mandatory and infectious disease specialists should be aware of this and adhere to practical guidelines. Prompt referral to and collaboration with multidisciplinary teams is a priority to improve treatment rates and survival.”

Disclosure: The researchers report no relevant financial disclosures.

Tuesday, January 29, 2013

Vertex hepatitis C drug revenues plummet

Investment Commentary

Vertex hepatitis C drug revenues plummet

Galen Moore
Web Editor- Boston Business Journal

Vertex Pharmaceuticals (Nasdaq: VRTX) saw sales of its hepatitis C drug, Incivek, drop off precipitously in the fourth quarter, year over year. The fast decline in Incivek sales, less than two years after its U.S. Food and Drug Administration approval in May of 2011, underscores the fast-moving competitive landscape for hepatitis C. 
Cambridge, Mass.-based Vertex and several other competitors are locked in battle to try to come up with an all-oral drug cocktail that would eliminate the need for interferon injections, which would improve patients’ quality of life. In the meantime, some patients are putting off treatment or joining clinical trials rather than starting Incivek or other already-approved medicines.
Continue Reading....

Of Interest
Chronic Hepatitis C Infection: Treat Now or Wait?
A collection of articles weighing the risks and benefits of treating HCV now or waiting for future therapies

Hepatitis Connect Presents An Interview With Alan Franciscus

Hepatitis C Connect
As once a patient myself, I understand the importance of finding the right HCV website that offers accurate information and support.
Once this is accomplished, its easier to overcome the anxiety, fear, and medical obstacles faced after being diagnosed with this life-altering disease. 
Hepatitis Connect is that site, a fresh resource for hepatitis C news, original articles and current information.  By joining Hepatitis Connect readers can connect with others and discuss  therapy, clinical trials or simply find support.  
Recently offered at Hepatitis Connect is an interview by patient advocate John Lavitt with the remarkable Alan Franciscus, Editor-in-Chief at HCV Advocate. You won't want to miss this three part series.
An Interview with Alan Franciscus of the Hepatitis C Support Project
There is a very good argument to be made that Alan Franciscus is the most significant trailblazer in his work for the hepatitis C awareness and advocacy movement in the United States. In 1997, Alan founded the Hepatitis C Support Project (HCSP) to help support and advocate for people affected by hepatitis C, hepatitis B, and HIV and hepatitis coinfections. HCSP has generated several essential support services and informational resources that have become an invaluable part of the current HCV landscape in America.

Hepatitis C - The Unspoken Epidemic

The Unspoken Epidemic

By India Perez-Urbano @ The Harvard Crimson

While the numbers for HIV/AIDS are still high, they have dropped dramatically since the 1980s and ’90s. Due to an uprising of powerful activists groups and community advocacy, HIV/AIDS was brought to the forefront of political and social issues. Meanwhile, Hepatitis C is on the opposite side of the spectrum. It has lacked a community of concerned individuals and has consequently had very little attention since 1989, when it was first discovered. Advocacy for Hepatitis C is practically dismal, especially compared to HIV/AIDS and Hepatitis B. Funding for Hepatitis C research and resources is virtually negligible. This is due to the fact that Hepatitis C is not only an unspoken topic, but it is also an incredibly complex topic....
Research has found that Hepatitis C is also most prevalent among the baby-boomer generation, the generation that lived through the “Summer of Love,” when experimentation with Schedule I drugs was especially high. Today, individuals who lived during that era have an HCV prevalence rate of more than double the national average. Targeting this generation is our best bet at drastically dampening the epidemic....
However, the “hippie” generation should not be our only focus. New statistics have shown that Hepatitis C is on the rise among American youth. In Massachusetts alone, HCV prevalence has risen from 65 cases per 100,000 between the ages of 15 and 24 in 2002 to 113 cases per 100,000 in 2009. This has been caused by to an increase in injection drug usage among America’s youth....
Continue reading.......

Cancer risk much greater among men

Cancer risk much greater among men

Male drinking and eating habits among reasons why they are 35% more likely to die from the disease than women

, health correspondent
The Guardian,
Men are 35% more likely to die from cancer than women, with men's drinking and eating habits, late diagnosis and advances in breast cancer treatment cited for the stark differential.
An analysis of the most recent UK deaths from cancer found that 202 out of every 100,000 men died from cancer in 2010 compared with 147 per 100,000 women.
When sex-specific forms of the disease are excluded, such as prostate, testicular and ovarian cancer, the gender gap is even wider, with men 67% more likely to die. And when only working age people are looked at men under 65 have a 58% greater chance of dying than women of the same age.
The sexes' respective likelihood of death varies depending on the type of cancer. Men are almost three times as likely as women to die of oesophageal cancer and almost twice as likely to die from liver cancer.
Tuesday Jan 29 2013
The fact that men are more likely than women to both develop and die from cancer has been covered by most of the media today.

The news is based on a report highlighting the excess cancer burden in men (both in terms of cases and deaths), and was produced by Cancer Research UK, the Men’s Health Forum and the National Cancer Intelligence Network.

Continue reading....

Janssen and Idenix - The Newest Hep-C Partnership

Investment Commentary

Source - The Motley Fool

A collaboration between Janssen and Idenix is the highlight of this video. The collaboration will evaluate combinations using the following investigational HCV drugs; simeprevir formerly referred to as TMC435 a protease inhibitor developed by Janssen R&D Ireland and Medivir, TMC647055 a polymerase inhibitor by Janssen and Idenix's IDX719 a NS5A inhibitor. The clinical hold on IDX184 in relation to the outcome of Bristol-Myers tragic trial with drug BMS-986094 is also included in the video.


New Interferon-free Development Program
Alan Franciscus
Editor-in-Chief, HCV Advocate
January 28 2013 - Medivir announced a collaboration between Medivir/Janssen and Idenix for the clinical development of multiple HCV inhibitors with and without ribavirin—all the studies will be interferon-free.
Continue reading....

Press Release
Medivir: Phase II all-oral combination studies of Simeprevir, TMC647055 and IDX719 for the treatment of Hepatitis C to be initiated shortly

CDC-Foodborne Disease Outbreaks - United States, 2009–2010

The CDC released a study today on foodborne illnesses via CDC’s Foodborne Disease Outbreak Surveillance System which reported;
During 2009–2010, beef, dairy, fish, and poultry were associated with the largest number of foodborne disease outbreaks.

What is added by this report?
Among the 1,527 foodborne disease outbreaks reported in 2009 and 2010, most outbreak-associated illnesses were caused by norovirus or Salmonella. Among outbreaks in which both an etiologic agent and single-commodity food vehicle were identified, most outbreaks were attributed to Campylobacter in unpasteurized dairy products, Salmonella in eggs, and Shiga toxin–producing Escherichia coli O157 in beef. The pathogen-commodity pairs responsible for the most outbreak-related illnesses were Salmonella in eggs (2,231 illnesses), in sprouts (493), and in vine-stalk vegetables (422).
 View the report;
This Week in MMWR

Surveillance for Foodborne Disease Outbreaks — United States, 2009–2010January 25, 2013 / Vol. 62 / No. 3

Surveillance for Foodborne Disease Outbreaks — United States, 2009–2010
Known pathogens cause an estimated 9.4 million foodborne illnesses annually in the United States. During 2009–2010, a total of 1,527 foodborne disease outbreaks (675 in 2009 and 852 in 2010) were reported in the United States via CDC’s Foodborne Disease Outbreak Surveillance System. This report summarizes findings from that surveillance....
Reported today online by The Associated Press 

NEW YORK (AP) -- A big government study has fingered leafy greens like lettuce and spinach as the leading source of food poisoning, a perhaps uncomfortable conclusion for health officials who want us to eat our vegetables.
Continue Reading.....

Reported online by USA Today

CDC: Beware the leafy green, poultry and dairy

Leafy greens such as lettuce, spinach and kale accounted for the most food-borne illnesses nationwide from 1998 through 2008, the Centers for Disease Control and Prevention reports.

Dairy products accounted for the most hospitalizations. The most deaths were linked to poultry.

The study isn't meant to be a "risk of illness per serving" list for consumers, said Patricia Griffin, a food-borne disease expert at the CDC who was the senior author of the report. The statistics are meant to help regulators and the food industry target efforts to improve the safety of food.

"The vast majority of meals are safe," she said, so don't let the numbers for leafy greens keep you from eating vegetables. "Eating them is so important to a healthy diet. They're linked to reduced risk of heart attacks, stroke and cancer."

The study looked at 4,887 outbreaks that caused 128,269 illnesses, hospitalizations and deaths when the food that caused them was known or suspected. It appears Tuesday in the journal Emerging Infectious Diseases.

Epidemiologists at the CDC found that leafy greens accounted for 23% of illnesses and dairy products 14%. However, when they looked only at hospitalizations, the lineup was different: Dairy products were responsible for 16% of hospitalizations followed by leafy vegetables at 14% and poultry 12%. For deaths, poultry accounted for 19%, then dairy products at 10%.

The overall number of deaths was small: 277 people died from food-borne illnesses linked to poultry and 140 from illnesses linked to dairy products during those years.

While the statistical details won't be all that helpful to consumers, it's "essential" for government agencies and the food industry as they work to make food safer, Griffin said.

That's especially the case now that implementation of the Food Safety Modernization Act is underway. The act requires the Food and Drug Administration to focus its regulatory efforts on the highest-risk food products. Until now, they were hard to identify.

Griffin cautions that the dairy product numbers are misleading. Many of the outbreaks linked to dairy products involve unpasteurized milk and cream, but the vast majority of Americans drink and eat only pasteurized dairy products.

"The weight of the raw milk outbreaks is making it look as if dairy is a bigger source of illness than we actually think it is," she said.

A study published last year that looked at 13 years of outbreaks linked to dairy products found that unpasteurized milk, cheese and cream were 150 times more likely to cause food-borne illness outbreaks than pasteurized dairy foods and that such outbreaks had a hospitalization rate 13 times higher than those involving pasteurized dairy products.                                                

No Added Benefit for Chemo Beads in Liver Cancer

No Added Benefit for Chemo Beads in Liver Cancer

By Charles Bankhead, Staff Writer, MedPage Today
Published: January 28, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

SAN FRANCISCO -- Outcomes in hepatocellular carcinoma (HCC) failed to improve after hepatic arterial embolization (HAE) with doxorubicin-eluting beads (LC Bead) versus beads without the drug (Bead Block), a randomized trial showed.

Patients treated with drug-free beads had an overall response rate of 11% compared with 6% of patients who received the drug-eluting beads. About 85% of patients in both arms had stable disease, reported Karen Brown, MD, reported Memorial Sloan-Kettering Cancer Center in New York City, and colleagues.

Progression-free survival (PFS) was slightly better with the beads alone, and HAE with the doxorubicin-containing beads led to a nonsignificant 3-month increase in overall survival (OS), said Brown at the Gastrointestinal Cancers Symposium.

"Doxorubicin-loaded drug-eluting beads did not improve response rate, median time to progression, progression-free survival, or overall survival in this randomized trial," she explained. "The addition of doxorubicin to the beads does not appear to increase toxicity or compromise safety."
"This study brings into question the added benefit of chemotherapy for embolization of hepatocellular carcinoma," she added.

HAE has established a role in the treatment of HCC, but chemoembolization has garnered more support among clinicians, largely without a complete understanding of the role chemotherapy might play in HAE.

Two studies published about a decade ago have provided the evidentiary basis for chemoembolization, Brown said. In particular, one study showed superior 1- and 2-year survival with chemoembolization versus embolization and conservative treatment in patients with unresectable HCC (Lancet 2002; 359: 1734-1739).

"There was a sequential design of the study that allowed for termination when there was a significant survival benefit demonstrated in either of the study arms [versus conservative care]," said Brown. "This occurred earlier in the transarterial chemoembolization group, so when the survival benefit was demonstrated in that group, the study was stopped."

She pointed out the the authors of that study acknowledged that there were not enough patients in the embolization group to draw definitive conclusions. "Nonetheless, over 10 years later, many people interpret this study as showing a survival benefit for transarterial chemoembolization compared with either embolization or best supportive care, which is not the case," she said.

Continuing with a comparative evaluation of the two HAE strategies, Brown's group recruited patients with Okuda stage I-II unresectable HCC and randomized them to embolization or to chemoembolization with beads containing 150 mg of doxorubicin.

The primary endpoint was objective response rate by RECIST criteria as determined from multiphase CT imaging performed 3 weeks after treatment. Disease progression or ≤5% tumor necrosis was considered treatment failure.

Secondary objectives included safety and tolerability, time to progression (TTP), PFS, OS, and an exploratory comparison of response and other outcomes between the two groups.

Data analysis included 92 patients. Brown reported five partial responses (11%) in the embolization group and three (6%) in the chemoembolization arm. Additionally, 40 (87%) patients in the embolization group had stable disease, as did 39 (85%) patients in the chemoembolization group.
Investigators also evaluated response by lesion, using European Association for Study of the Liver criteria. The analysis included 171 lesions. The results showed a 100% decrease in 58% of lesions with embolization versus 61% of lesions treated with chemoembolization.

The proportion of lesions that decreased in size by more than 50% were 24% with embolization and 27% with chemoembolization, and 17% versus 11% of lesions in the respective groups decreased by less than 50%. One lesion in each group increased in size by more than 20%.

Analysis of secondary endpoints showed no significant differences between the groups:
  • 2-year probability TTP: 42% with embolization versus 49% with chemoembolization
  • 2-year probability PFS: 11% versus 19%
  • PFS: 5.2 months versus 4.6 months
  • OS: 16.6 versus 19.6 months
There was no difference in adverse events at 84% in both groups. The most common adverse event was postembolization syndrome of pain, fever, nausea, or vomiting.

Given current epidemiologic trends in HCC, the results have clear implications for management of the disease, said Françoise Mornex, MD, PhD, of Lyon University Hospital in France.

"The incidence of HCC is increasing everywhere in the world, so we need to find the best treatments and we need to optimize treatment," said Mornex, who was not involved in the study. "There are several methods to embolize and treat these patients, and we still don't know which is the best one, so this question is important, and these results in 100 patients are quite robust."

But she cautioned that questions still remain. "Should we reproduce these results with a larger cohort of patients? Should we believe in these results and change our practice directions? I'm not sure we should change our practice on the basis of one study, even if the study is very important," Mornex said.

Clinicians should consider the results and how they might fit into their own practice and then integrate the information as appropriate, she added.

Primary source: Gastrointestinal Cancers Symposium
Source reference:
Brown KT, et al "A randomized, single-blind, controlled trial of beads versus doxorubicin-eluting beads for arterial embolization of hepatocellular carcinoma (HCC)" GiCS 2013; Abstract 143.

Pegylated interferon- Pegasys, PegIntron similarly effective for chronic HCV genotype 1

*pegylated interferon alfa-2a (Pegasys) and alfa-2b (PegIntron)

Pegylated interferon alfa-2a, 2b similarly effective for chronic HCV genotype 1

Coppola N. BMC Infect Dis. 2012;doi:10.1186/1471-2334-12-357.

January 29, 2013

Standard doses of pegylated interferon alfa-2a  and alfa-2b, administered with ribavirin, were similarly effective in patients with chronic hepatitis C genotype 1 in a recent study.

Researchers performed meta-analysis of seven studies evaluating the efficacy of peginterferon-alfa-2a (Peg-IFN a-2a) and 2b (Peg-IFN a-2b) in 3,026 patients with chronic hepatitis C genotype 1. Five prospective randomized trials and one prospective and one retrospective nonrandomized trial were included. All participants were treatment-naive and anti-HIV-negative.

Study quality was measured according to the Chalmers and Jadad scales. Scores on the Chalmers scale ranged from 0.2 to 0.6 (mean of 0.43) overall, from 0.11 to 0.58 (mean 0.36) for the protocol, and from 0.23 to 0.67 (mean 0.53) for data analysis and presentation. On the six-point (0-5) Jadad scale, two studies scored 0, two scored 1 and three scored 3.

Rapid virological response (RVR) was evaluated in four studies in 2,729 patients, and occurred at similar rates among patients taking alfa-2a and 2b (RR=1.05; 95% CI, 0.87-1.27). Sustained virological response (SVR) rates, measured in 2,646 patients across six studies, also were similar for the treatments (RR=1.08; 95% CI, 0.99-1.18).

Early complete virological response (EVR) and end-of-treatment response (ETR) were assessed in five studies each, in 2,766 and 2,460 patients, respectively. EVR and ETR were more common among alfa-2a recipients (RR=1.12, 1.03-1.22 for EVR; RR=1.22, 1.14-1.31 for ETR).
Sensitivity analysis excluding nonrandomized and poor-quality studies did not significantly impact results.

“The data show that there is no difference between the two treatments in the achievement of RVR and SVR; the higher rates of EVR and ETR in the patients treated with Peg-IFN a-2a are clearly of lesser clinical impact,” the researchers wrote. “The datum on SVR may be considered the most important result from this meta-analysis. … Peg-IFN a-2a and Peg-IFN a-2b, both in combination with ribavirin … can be used indifferently for patients with genotype 1 chronic hepatitis C who are anti-HIV-negative and naïve to antiviral treatment.”

Scientists Discover Process That Turns Normal Liver Cells to Cancer Cells

Scientists Discover Process That Turns Normal Liver Cells to Cancer Cells

Jan. 28, 2013 — A team of scientists from the Cancer Science Institute of Singapore (CSI) at the National University of Singapore (NUS) has identified a genetic process in which normal liver cells transform into cancerous ones.

The finding provides new understanding into the pathogenesis of human cancers.The team, which also includes researchers under the direction of Professor Guan Xin-Yuan at The University of Hong Kong, is the first to provide direct evidence that the "editing" of this protein-making sequence promotes the development of cancer.
Normally, deoxyribonucleic acid (DNA), which comprises the genetic code, serves as a template for production of ribonucleic acid (RNA) in precise fashion such that the DNA code and RNA code are identical. Editing is the process in which the RNA is changed after it is made from the DNA, resulting in production of an altered gene product.

This novel study, which was conducted from June 2010 to November 2012, was first published in the online version of Nature Medicine on 6 January 2013.

Focus on RNA
The development of liver cancer is believed to be a multi-step process, in which genetic and epigenetic alterations build up. However, it is much easier technically to detect genetic mutations through DNA sequencing. Epigenetic changes, which by definition do not involve changes in DNA sequence, have not been as well defined because it is much more difficult technically to identify them and demonstrate their role in cancer.

While recent use of next-generation sequencing of DNA and RNA have been suggestive, no apparent causal relationship between the levels of RNA editing, a process of altering RNA sequences, and cancer progression was thought to exist -- until now. As such, RNA editing is a novel epigenetic alteration in cancer.

Recognising the importance of molecular mechanisms that underlay the development of liver cancer, the research team studied the roles that RNA plays in the formation of proteins to carry out functions within the body. The researchers are the first to clearly link the RNA editing event of a protein to be significantly associated with the development of liver cancer.
Professor Daniel Tenen, Director of CSI and Principal Investigator for the study, said, "Up to now, scientists have focused on studying DNA, not RNA. Because RNA can be more easily modified than DNA, it suggests that therapeutic approaches are potentially available."

RNA Editing Process Changes Protein
In the study, the researchers performed genomic analysis of three pairs of tissue samples, each pair comprising a sample of liver cancer tissue and an adjacent non-tumour tissue, from surgical specimens of liver cancer patients.

They found that the RNA editing of a specific gene known as antizyme inhibitor 1 (AZIN1) was much higher in the tumour samples. They discovered that this editing process was catalysed by an enzyme called adenosine deaminase acting on RNA-1 (ADAR1), which changed the product of the AZIN1 protein to a form which promoted the development of cancer.

To verify their findings, the team repeated the tests on paired tissue samples of some 180 liver cancer patients.

The results obtained were consistent with the initial genomic analysis, indicating that the RNA editing of the AZIN1 gene in tumours is significantly associated with the presence of liver cirrhosis, tumor recurrence, and poorer survival rate.

Said Dr Polly Chen, Research Assistant Professor at CSI, and the lead author of the research team, "We believe that there is high possibility that the findings are applicable to other cancers, but further studies are required to ascertain this."

The Next Step
Moving forward, Prof Tenen and Dr Chen will investigate the characteristics of AZIN1 and ADAR1 to further understand their impact on tumour development. They also intend to look at these mechanisms in other cancers. They will also work on ways to correct the RNA editing process so as to block the cells' conversion from normal to malignant.

Both scientists hope that their findings will provide the medical community with a useful biomarker that can be used to detect early disorders leading to liver cancer, and even other forms of cancer, before clinical symptoms become apparent.

Predicting survival among those aging with HIV infection

Predicting survival among those aging with HIV infection

By Helen Dodson

A new collaborative study led by Yale, the VA Healthcare System, and the North American Cohort Collaboration supports the accuracy of an index used for predicting mortality as patients with HIV age. The study appears in the Journal of Acquired Immune Deficiency Syndromes (JAIDS).

The course of chronic HIV infection has changed with the advent of antiretroviral therapy (ART). Viral suppression is common, the authors write, and there have been reductions in AIDS-related deaths in regions where ART is easily accessible. Yet, the authors say, people with HIV infection continue to experience a higher rate of mortality due not just to HIV-related factors, but because chronic HIV infection appears to exacerbate vulnerability to aging-related organ system injury.

The Veterans Aging Cohort Study (VACS) Index, funded by the National Institutes of Health (NIH), builds upon older indices that measured biomarkers for HIV (the virus that causes AIDS) — such as CD4 cell count, HIV-1 RNA levels, and patient age — in order to determine mortality risk. The newer VACS Index takes other critical factors into account, such as the increasing role of multi-organ system injury and hepatitis C infection, and the decreasing role of other factors such as CD4 count.

The researchers analyzed data from over 5,000 veterans and over 10,000 non-veterans representing 14 separate cohorts of HIV-infected patients around the country who had had at least a year of exposure to ART. They followed up with those patients for just over three years. Researchers found the new VACS index to be much more accurate and effective than an index restricted to CD4 count, HIV-1 RNA, and age.

According to senior author Dr. Amy Justice, professor of internal medicine at Yale School of Medicine, “The VACS Index accurately estimates risk of mortality among those aging with HIV infection whether they live in Canada or the United States. Further, it is accurate among men and women, those who are older and younger, and white individuals and people of color.” The team has developed an app that allows patients and their providers to use this information in care. It can be accessed online.

Justice is professor of medicine and public health at Yale School of Medicine; she also serves as section chief of general internal medicine in the VA Connecticut Healthcare System and is affiliated with Yale’s Center for Interdisciplinary Research on AIDS.

This study was supported by grants from the National Institutes of Health. Other funding was provided by the Training Program in Environmental Epidemiology, and other grants from the NIH. This work was also supported by the Centers for Disease Control, the Canadian Institutes for Health Research, and the Canadian Trials Network.

Other authors are Janet Tate of Yale and the VA Healthcare System, West Haven; Sharada P. Modur, Keri N. Althoff, Lisa P. Jacobson, Kelly A. Gebo, Richard Moore, Gregory D. Kirk and Stephen Game of Johns Hopkins University; Mari M. Kitahata of the University of Washington; Michael A. Horberg of the Mid-Atlantic Permanente Research Institute; John Brooks and Kate Buchacz of the Centers for Disease Control; James Goedert of the National Institutes of Health; Sean Rourke and Anita Rachlis of the University of Toronto; Sonia Napravnik and Joseph Eron of the University of North Carolina Chapel Hill; Ronald Bosch of Harvard Medical School; James H. Willig of the University of Alabama; Benigno Rodriguez of, Case Western Reserve University; Robert Hogg of Simon Fraser University in Vancouver; Marina Klein of McGill University in Montreal; John Gill of the University of Calgary; Steven Deeks of the University of California San Francisco; Timothy Sterling of Vanderbilt University; Kathryn Anastos of Einstein Medical School; and the NA-ACCORD and VACS Project Teams.

National Hepatitis C Survey Prompts Call for All Canadian Boomers to Get Tested

Information gaps may be compromising optimal diagnosis and treatment

TORONTO, Jan. 29, 2013 /CNW/ - Current realities of chronic hepatitis C in Canada and results of a new national survey of physicians and Canadians on awareness of the liver disease, have prompted the Canadian Liver Foundation (CLF) to urge general practitioners (GPs) to immediately begin recommending a one-time blood test for all adults born between 1945 and 1975.
"We know that risk-based testing has not been effective in identifying all infected adults, and most physicians surveyed agree they do not screen enough patients for hepatitis C," said Dr. Morris Sherman, Chairman of the CLF and hepatologist at Toronto General Hospital. "Given that today's treatments can cure a majority of those infected, it's time to be proactive at identifying chronic hepatitis C in the age group with the highest prevalence. The hepatitis C antibody test is inexpensive and is covered by all provincial health care plans."

According to the survey, conducted by Ipsos Reid, 83 per cent of GPs agree that patients would benefit from more routine screening. GPs also admit to having a limited understanding of the disease and its treatment. Only 35 per cent feel they know a lot about symptoms and nearly four in 10 (38 per cent) feel they know nothing at all or not much about available treatments. More than half (57 per cent) are unaware that hepatitis C can be cured.

Focus on Boomers
While anyone can be exposed to hepatitis C, Canadian data show that chronic hepatitis C is most pervasive among those born between 1945 and 1975.1 Baby boomers are up to five times more likely to be infected by hepatitis C than other adults.2 Yet Canadian boomers are less likely than younger generations to have been tested, according to the survey. Additionally, boomers claim to be the most knowledgeable generation about hepatitis C, but scores from the survey show they know the least.
"Hepatitis C is a silent disease, meaning often symptoms don't appear for many years until the liver is severely damaged," said Dr. Marc Bilodeau, hepatologist and Associate Professor of Medicine at Université de Montréal. "The large number of people infected, the asymptomatic nature of the disease and the serious consequences associated with it justify broader testing. The good news is nearly all Canadians would accept being tested if suggested by their doctor."

The CLF extended the recommendation for testing beyond the boomer generation, taking into account immigration from countries where hepatitis C is more widespread and common.
While nine in 10 Canadians believe that someone can have hepatitis C and not know it, this is not leading to testing. In fact, while over 300,000 Canadians are living with chronic hepatitis C and an estimated 71,000 Canadians are living with HIV,3 more are being tested for HIV/AIDS (32 per cent) than hepatitis C (23 per cent) according to the survey.

Survey Design and Methodology
The results of the survey, completed in September 2012, are based on 1,000 online interviews conducted nationally with adults over the age of 18 and 300 online interviews with GPs. The sample was generated by Ipsos Reid's Canadian Online Panel to reflect the Census data for Canadian adults and the national distribution of Canadian GPs.4
With the given sample size, the poll is accurate within +/- 3.5 percentage points for all Canadians and +/- 6.5 percentage points for all GPs, 19 times out of 20 had the entire adult population and all GPs been polled.5
The survey was conducted by Ipsos Reid on behalf of the Canadian Liver Foundation. The Canadian Liver Foundation acknowledges Merck Canada for its support of the Canadian Liver Foundation's campaign to raise awareness of hepatitis C as a serious liver disease and promote liver health.

About Hepatitis
Hepatitis C is a serious and potentially fatal liver disease. More than 300,000 people in Canada are living with chronic hepatitis C but many are unaware of it.6 It can take decades after individuals are infected for symptoms to appear.7 Undiagnosed and untreated chronic hepatitis C can lead to cirrhosis, liver cancer, liver failure or the need for a liver transplant.8

People can contract hepatitis C through any blood-to-blood contact including injection drug use (even a single episode), blood transfusions prior to 1990, participation in medical procedures or immunization in countries where hepatitis C is common, sharing personal care items (razors/nail clippers), and tattoos and piercings with improperly sterilized equipment.9

The CLF is encouraging GPs to learn more about screening and testing for hepatitis C. Tools to help physicians screen, diagnose and treat hepatitis C are available at Canadians looking for more information on hepatitis C can also visit the CLF website at

About the Canadian Liver Foundation
Founded in 1969 by a group of doctors and business leaders concerned about the increasing incidence of liver disease, the CLF was the first organization in the world devoted to providing support for research and education into the causes, diagnoses, prevention and treatment of all liver disease. Through its chapters across the country, the CLF strives to promote liver health, improve public awareness and understanding of liver disease, raise funds for research and provide support to individuals affected by liver disease.
An Audio News Release is available here:
B-roll is available here:
A short video on boomers and hepatitis C is available here:
1 Canadian Liver Foundation. Accessed January 4, 2013.
2 Chronic Hepatitis C: Why Baby Boomers Should Get Tested. Accessed January 4, 2013.
3 UNAIDS. Accessed on January 4, 2013.
4 Ipsos Reid.
5 Ibid.
6 Canadian Liver Foundation. Accessed January 4, 2013.
7 Health Canada. Accessed January 4, 2013.
8 Public Health Agency of Canada. Accessed January 4, 2013.
9 Canadian Liver Foundation. Accessed January 4, 2013.