April 11, 2012

Promising Vaccine Targets On Hepatitis C Virus

ScienceDaily (Apr. 3, 2012) — A team led by scientists at The Scripps Research Institute has found antibodies that can prevent infection from widely differing strains of hepatitis C virus (HCV) in cell culture and animal models.

HCV's very high rate of mutation normally helps it to evade its host's immune system. The newly discovered antibodies, however, attach to sites on the viral envelope that seldom mutate. One of the new antibodies, AR4A, shows broader HCV neutralizing activity than any previously reported anti-HCV antibody.

"These antibodies attach to sites on the viral envelope that were previously unknown, but now represent promising targets for an HCV vaccine," said Mansun Law, an assistant professor at Scripps Research. Law is the senior author of the new report, which appears online this week in the Proceedings of the National Academy of Sciences.

A Desperate Need

An effective HCV vaccine is desperately needed. The World Health Organization (WHO) estimates that the virus has established mostly silent infections in 130 to 170 million people worldwide -- nearly 3 percent of the human population -- and spreads to 3 to 4 million new people annually. HCV principally infects liver cells, and is thought to cause chronic, often-unnoticed liver inflammation, which eventually can lead to serious liver ailments. The virus already is responsible for about a quarter of annual US cases of liver cirrhosis and primary liver cancer, and it is the leading cause of liver transplants. In some developing countries, HCV prevalence is extremely high; studies suggest that in Egypt, as many as 22 percent of the population is infected -- apparently due to poor screening of blood products and past re-use of syringes. Even in developed countries, HCV infections represent a looming public health crisis. In the United States and Europe, up to 14 million people are now HCV-positive, and each year an estimated 150,000 people are newly infected.

The current leading treatment for HCV infection involves a 12- to 36-week course of the immune-stimulating protein interferon-alpha, the antiviral drug ribavirin and HCV protease blocker. But it is not completely effective, and it causes significant adverse side effects -- aside from being very expensive. To fully stamp out the HCV pandemic, especially in developing countries, scientists will have to develop a cheap preventive vaccine.

Yet an effective HCV vaccine has so far been elusive. The virus mutates very rapidly, and thus, antibodies raised against one isolate of HCV typically won't protect against a subsequent HCV infection. Hospital samples of HCV suggest that the virus's genes, and the proteins for which they code, are highly variable even within an individual patient.

"One of the big goals of HCV vaccine development has been to find an accessible spot on the virus that doesn't change constantly," said Law.

Searching for Vulnerabilities

To find such vulnerable spots, researchers sift through antibodies sampled from infected people and look for those antibodies that can neutralize a broad range of viral strains. The locations on the virus where those broadly neutralizing antibodies bind mark the vulnerable viral structures that can be used as the bases of a broadly effective, antibody-stimulating vaccine. Previous studies, including a 2008 study in Nature Medicine, for which Law was lead author, have found some broadly neutralizing HCV antibodies. But for the present study, Law and his colleagues used a more thorough approach, known as "exhaustive panning," to see if they could find new and even more broadly neutralizing antibodies. "Exhaustive panning is a powerful technique for finding rare antibodies that might otherwise go undetected," Law said.

HCV employs a complex of two envelope glycoproteins, E1 and E2, to grab and fuse with target cells. Erick Giang, a research assistant in Law's lab, harvested this viral E1-E2 complex from HCV-producing cells in a lab dish and used it as "bait" for a panel of antibodies derived from the blood of a person with chronic HCV infection. The exhaustive panning technique involves exposing this bait protein to different anti-HCV antibodies in sequence, so that the known antibody-binding sites on the complex are progressively covered until only new ones are left.

In this way, Giang catalogued 73 new anti-HCV antibodies, which bind to five distinct "antigenic regions" on the E1-E2 complex. In standard cell culture tests of HCV-neutralizing ability, several of these antibodies showed an ability to neutralize infection by a wide range of HCV strains. One, AR4A, turned out to bind to an almost-unvarying spot on E1-E2 complex, close to the surface of the virus's outer coat of fat molecules. AR4A showed significant neutralizing ability against all 22 HCV strains in a test panel -- not only in tests in Law's lab, but also in confirmatory tests at the University of Copenhagen.

The Broadest Neutralizing Activity Yet

The new antibody thus is more broadly protective than the previous top contender, AR3A, which Law described in his 2008 Nature Medicine paper. "This human antibody AR4A has the broadest HCV-neutralizing activity known to the field," Law said.

Collaborating researchers at Rockefeller University, who recently engineered a line of HCV-infectable mice, showed that AR4A antibodies protected these mice from two widely different HCV strains. A combination of half-doses of AR3A and AR4A antibodies worked less well.

The next step for Law and his colleagues is to start making and testing prototype vaccines based on the vulnerable HCV binding sites that have been revealed by these antibody studies. The researchers also plan to use the new antibodies to study the structure and function of HCV proteins such as the all-important E1-E2 complex.

Anti-HCV antibodies such as AR4A and AR3A could have some therapeutic use, too. Although they wouldn't be able to clear existing HCV infections and would be too expensive and difficult to use on a large population to prevent new infections, they could be useful in preventing new HCV liver infections in liver transplant patients. Such infections can spread from HCV reservoirs in the patient's body to the newly transplanted liver tissue.

"Antibody-based treatment has worked extremely well for liver transplants to patients with hepatitis B virus, and we hope the new HCV antibodies can be just as helpful to HCV liver transplant patients," Law said.

In addition to Law and Giang, contributors to the paper, "Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus," were Marcus Dorner, Charles M. Rice, and Alexander Ploss of Rockefeller University in New York; Jannick C. Prentoe and Jens Bukh of the University of Copenhagen; Matthew J. Evans of the Mount Sinai School of Medicine; and Marlène Dreux and Dennis Burton at Scripps Research.

The Law laboratory's research is supported by the National Institutes of Health.

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Turning Lymph Nodes Into Liver-Growing Factories

liver

If your liver fails, having 40 small but functional livers scattered around your body might be the next best thing.

by Adam Piore

From the March 2012 issue; published online April 11, 2012

For people suffering from advanced liver disease, the prognosis is bleak. In many patients, such as those with cirrhosis, the liver becomes so clogged with scar tissue that healthy cells are choked off, preventing it from fulfilling its role of filtering toxins. The only cure is a liver transplant. Yet with just 6,000 available organs for some 100,000 patients each year, chances of winning the liver lottery are slim. And if you’re elderly or suffering from another disease, the chances are closer to zero.

But a surprising new technique under development by University of Pittsburgh stem cell researcher Eric Lagasse may radically improve those odds. Lagasse, based at Pitt’s McGowan Institute for Regenerative Medicine, has discovered how to turn any one of the body’s 500 lymph nodes—the small, oval-shaped organs where immune cells gather to fight invading pathogens—into an incubator that can grow an entirely new liver. Creating a whole set of miniature new livers might take as little as obtaining liver cells from healthy donors and placing them inside the lymph nodes of patients suffering from liver disease.

The concept was born in 2007, while Lagasse was pondering how to overcome a major roadblock to liver regeneration—in those with liver disease, the organ forms scar tissue that destroys its ability to heal. But then he noticed emerging evidence that transplanted liver cells could survive in unusual areas of the body, for instance under the renal capsule, a fibrous layer that protects the kidney from trauma. Lagasse reasoned that if he could implant liver cells away from the diseased organ, instead of succumbing they just might multiply and thrive.

So he set to work trying to grow liver cells outside the dying organ. As his test tube, he used mice with end-stage liver disease, implanting liver cells, or hepatocytes, from another mouse into their kidney capsules, under the skin, and into the spleen. Most of the mice died within eight weeks, the usual prognosis for end-stage liver failure in mice. But that changed when Lagasse injected cells into the belly: The mice gained weight, recovered energy, and within weeks appeared healthy.

After watching those mice thrive for several months, Lagasse repeated the experiment using fluorescent markers to trace the path of the liver cells. To his surprise, they had migrated to lymph nodes, where they grew to form large nodules that, in aggregate, reached a mass capable of keeping the animal alive.

It actually made sense. In many ways, lymph nodes are ideal bioreactors for growing new livers. They have an unusual capacity to expand, allowing them to accommodate an entire organ. They have ready access to the bloodstream, which nurtures new cells with nutrients as well as hormones and signaling agents needed for growth. And since the body has many lymph nodes, some can sacrifice their traditional duties to grow livers. The injections were so successful, Lagasse realized, because the belly provided enough space for cells to migrate.

Further experimentation showed Lagasse that if he injected hepatocytes directly into the lymph nodes, the cells picked up signaling proteins (essentially SOS signals to grow) released into the bloodstream from the dying liver. “There is communication between the new and a diseased liver,” Lagasse says. “They share some functions. We don’t totally understand the signaling mechanism, but we don’t need to if it works.”

Using his technique in mice, Lagasse has already succeeded in growing 20 to 40 small livers that gradually pick up the slack as the central liver fades. Together the mini-livers add up to 70 percent the size of a normal liver.

So far, Lagasse has not seen adverse reactions in his experimental mice. Rejection is not a problem because the animals were genetically engineered to share identical DNA, eliminating the risk that the immune system would attack foreign hepatocytes. In humans, Lagasse is banking on immunosuppressant drugs to prevent rejection. Further ahead, he is looking to an emerging technology known as induced pluripotent stem cells (iPSCs), in which adult cells are reprogrammed to be like embryonic stem cells so they can transform into any type of cell. Doctors could then collect blood or skin cells from a patient and turn them into healthy liver cells, enabling patients to be their own donors.

Even if rejection can be controlled, patients gravely ill from end-stage liver disease might succumb to surgery itself. To address this, Lagasse has injected hepatocytes into lymph nodes in peripheral parts of a mouse’s body—under the knee or arm—because that requires less invasive surgery. Growing a liver behind a knee is not ideal; in humans it might cause a bump weighing more than a pound in an inconvenient spot. But cultivating a liver in these peripheral areas could allow a very sick patient to survive long enough to recover the strength to undergo implantation in a more practical location.

Next Lagasse plans to replicate his experiments in pigs and hopes to implant human patients within the next few years. In principle, there’s no reason the approach should be limited to livers. “We’re talking about bioreactors that could grow any number of tissues inside the body,” Lagasse says. “This could work for any organ that secretes things or produces cells.” The thymus and pancreatic cells may be future candidates.

Stem cell expert Robert Lanza, who heads scientific research at Advanced Cell Technology in Massachusetts, calls the research an “exciting, novel idea.” But he sounds notes of caution. Liver cells carry out hundreds of different functions, only some of which Lagasse has tested in mice, and it is unlikely that transplanted cells could fulfill all of them in humans. “Also, you can envision all sorts of locations where it would not be good to have these cells,” he says. “What if they migrate to the lungs or brain?”

Lagasse concedes the many hurdles that lie ahead, not the least of which is convincing people that his bizarre transplantation technique might work. “This is such a wild idea, we need to demonstrate it could actually be used on a patient,” Lagasse says. “Still, I’ve spoken to many surgeons who are very excited about it.”

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Provided by NATAP

from Jules: The annual European liver meeting EASL, European Association for the Study of the Liver, starts April 18 where there will be new data on numerous oral HCV drugs in various stages of development and on new interferon-free oral HCV drug therapies. There are several presentations on Gilead's GS-7977, the new potent nucleotide inhibitor. A press release already announced this week Abbott's 95% SVR rate with only 12 weeks therapy in genotype 1 treatment-naives in 2 small studies with 3 HCV drugs, their potent protease ABT450 + a NNRTI, either ABT333 or ABT072, plus ribavirin. Abbott reported a 47% SVR rate in treatment-experienced patients with the same regimen, so for these patients more potent therapy regimens will have to be put together. There was a leak in data reported online by analysts this week, because much of the data is embargoed until presented at the conference, on the end-of-treatment data after 12 weeks therapy with the 2-drug combination of BMS' potent NS5A inhibitor daclatasvir+GS7977, where online analysts reported 97% of genotype 1 treatment-naive patients had undetectable virus after 12 weeks of treatment. There are several additional important new HCV drugs for which updates are expected including Roche's protease danoprevir boosted with low dose ritonavir, Boerhinger Ingelheim's protease BI201335 & their NNRTI BI207127, TMC435 the potent protease from Janssen, alisporivir the potent cyclophillin inhibitor. In phase 3 development, the last stage before FDA approval are daclatasvir, BI201335, TMC435, Alisporivir & already started or about to start for GS7977, with others quickly planning to move ahead fast as well. There will also be an update on a the 3-drug oral regimen of BI201335+BI207127+ribavirn. And of course there will be more updates & reports at EASL on additional new HCV drugs in development. At this point in development there are 5 major classes of new oral HCV drugs that are poised to be used in various combinations that include protease inhibitors, NS5A inhibitors, nucleotides, NNRTIs, and cyclophillin inhibitor, and ribavirin is still being used in some combinations. To leave you with one last thought: these 2 data leaks above report 95% SVR rates in small interferon-free multi-drug oral drug combinations of only 2 or 3 drugs, so is this the new standard of care that all future regimens will have to match for treatment-naives?? Roche, BMS, Gilead, Vertex, Abbott & Merck (also Idenix & Achllion, 2 smaller biotechs) each have several new HCV oral drugs at various stages of development, so are developing their own multi-drug interferon-free oral regimen with or without ribavirin.

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HCV Treatment May Improve Insulin Resistance in Nondiabetics

From Reuters Health Information

By Will Boggs MD

NEW YORK (Reuters Health) Apr 09 - In nondiabetics with hepatitis C virus (HCV), insulin resistance (IR) may improve once the virus is treated - regardless of whether the treatment is successful, researchers say.

They pointed out in a recent paper that HCV infection is an independent risk factor for incident diabetes, particularly when other risk factors for diabetes are present. It may be, they suggest, "that individuals with higher degrees of IR may benefit from receipt of HCV therapy in an attempt to decrease their risk of clinical sequelae of IR."

"Host factors, especially obesity, play a great role in insulin resistance in the HCV population, similar to other populations, but HCV therapy appears to also decrease insulin resistance irrespective of sustained virologic response," Dr. Mandana Khalili from University of California San Francisco told Reuters Health in an email.

Dr. Khalili and colleagues used direct measurements of insulin sensitivity to evaluate the impact of insulin resistance on achieving a sustained virologic response (SVR) to HCV therapy -- and the impact of HCV eradication on insulin resistance. As a control group, they used patients with HCV who did not receive antivirals.

Fifty nondiabetic HCV patients ages 18 to 60 - including 23 on pegylated interferon and ribavirin -- participated in the study, as reported online March 7 in Diabetes Care. At baseline, rates of insulin resistance were statistically similar in patients who did and did not receive antivirals.

There were 14 SVRs, with significantly higher rates in patients with genotypes 2 and 3 (83%) than in those with genotype 1 (36%; p=0.03).

Host and viral factors were similar among patients who did and did not achieve SVR, and the odds of achieving SVR did not differ with the degree of insulin resistance before treatment, regardless of genotype.

Six months after HCV therapy ended, insulin resistance (as measured by steady state plasma glucose) improved among patients who received anti-HCV therapy - although wide confidence intervals, possibly related to the small sample size, meant the difference was not statistically significant.

Specifically, SSPG decreased by 36 mg/dL in those with SVR and by 28 mg/dL in those without SVR, compared with the untreated group.

On multivariate analysis, the improvement in insulin resistance did not differ significantly between patients who did and did not achieve SVR.

As expected, increasing BMI was associated with higher levels of insulin resistance and with higher fasting glucose levels. Interferon use was positively associated only with insulin resistance.

"The main purpose of this study was to evaluate the influence of insulin resistance on SVR as well as SVR on improvement of insulin resistance," the researchers note. "When using precise measurements of insulin resistance, insulin resistance did not appear to be substantially associated with achievement of SVR. Successful viral eradication did not appear to substantially influence insulin resistance when compared with HCV therapy that does not result in SVR."

They added, "Similar to other studies using the direct measurements of insulin resistance, our study is limited by small sample size, which may not have allowed for detection of other known host and viral factors that influence SVR."

"Any patient who is a candidate for HCV therapy should be considered for therapy, especially considering the more recent effective anti-HCV therapy regimens," Dr. Khalili said. "However, those who have known risk factors associated with insulin resistance, especially obesity, should address these factors (including weight loss) first, since they have a much higher impact on decrease in insulin resistance, but they should also be considered for HCV therapy."

"We are currently evaluating a large cohort of HCV patients to describe the distribution and variability of insulin resistance in an ethnically diverse HCV population," Dr. Khalili added.

"Further studies are necessary to determine if additional changes in insulin resistance occur after successful viral eradication beyond six months after discontinuation of HCV therapy," the investigators say.

SOURCE: http://bit.ly/HqxE67

Diabetes Care 2012.

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Provided by Infection Control Today (ICT)

Chronic hepatitis C (HCV) disease can be complicated with comorbid conditions that may impact treatment eligibility and outcomes. The aim of the study by Louie, et al. (2012) was to systematically review comorbidities and symptoms in an HCV-infected population, specifically assessing comorbidities associated with HCV antiviral treatment and disease, as well as comparing comorbidities between an HCV-infected and uninfected control population.
This was a retrospective cohort study within a United States medical claims database among patients with chronic HCV designed to estimate the two-year period prevalence of comorbidities. Patients with two HCV diagnosis codes, 24 months of continuous health insurance coverage, and full medical and pharmacy benefits were included.

Among a chronic HCV cohort of 7,411 patients, at least one comorbid condition was seen in almost all patients (>99%) during the study period. HCV-infected patients reported almost double the number of comorbidities compared to uninfected controls. Of the 25 most common comorbidities, the majority of the comorbidities (n = 22) were known to be associated with either HCV antiviral treatment or disease. The five most frequent comorbidities were liver disease [other] (37.5%), connective tissue disease (37.5%), abdominal pain (36.1%), upper respiratory infections (35.6%), and lower respiratory disease (33.7%). Three notable comorbidities not known to be associated with antiviral treatment or disease were benign neoplasms (24.3%), genitourinary symptoms & ill-defined conditions (14.8%), and viral infections (13.8%).

The researchers concluded that this U.S. medically insured HCV population is highly comorbid. Effective strategies to manage these comorbidities are necessary to allow wider access to HCV treatment and reduce the future burden of HCV disease and its manifestations. Their research was published in BMC Infectious Diseases.

Reference: Louie KS, et al. The high comorbidity burden of the hepatitis C virus infected population in the United States. BMC Infectious Diseases 2012, 12:86 doi:10.1186/1471-2334-12-86

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Management of Anemia in Patients Receiving Protease Inhibitors

Gastroenterology & Hepatology Volume 8, Issue 4 April 2012

Stephen A. Harrison, MD, LTC, MC
Chief of Hepatology
Brooke Army Medical Center
Clinical Associate Professor of Medicine
University of Texas Health Science Center at San Antonio
San Antonio, Texas

G&H How frequently does anemia occur in patients who are receiving protease inhibitor–based therapy?

SAH Anemia occurs frequently in these patients—certainly more frequently than it does in patients receiving only pegylated interferon and ribavirin. In a pooled analysis of the clinical safety data from trials of telaprevir (Incivek, Vertex), hemoglobin values less than 10 g/dL were found to occur in approximately 36% of patients receiving telaprevir-based triple therapy. More severe anemia, defined as hemoglobin values less than 8.5 g/dL, was observed in about 14% of patients. Among patients treated with pegylated interferon and ribavirin alone, only 17% had hemoglobin values less than 10 g/dL, and 5% had hemoglobin values less than 8.5 g/dL.

Similar rates of anemia were seen in trials of boceprevir (Victrelis, Merck). Pooled data from SPRINT-1 and SPRINT-2 showed that approximately 49% of patients had hemoglobin values less than 10 g/dL, and approximately 6% of patients had hemoglobin values less than 8.5 g/dL. Similar rates of anemia were observed in RESPOND-2, a trial that evaluated boceprevir-based triple therapy in interferon-experienced patients: Approximately 49% of these patients had hemoglobin values less than 10 g/dL, and approximately 10% of patients had hemoglobin values less than 8.5 g/dL. Among patients in the control group, who were treated with pegylated interferon and ribavirin alone, approximately 30% of patients showed a hemoglobin value less than 10 g/dL, and only approximately 3% of patients had a hemoglobin value less than 8.5 g/dL. Overall, there is a significantly higher rate of clinically significant anemia when therapy includes either boceprevir or telaprevir compared to treatment with pegylated interferon and ribavirin alone.

G&H Are rates of anemia similar between these 2 protease inhibitors?

SAH Yes, rates of anemia seem to be fairly similar with both telaprevir and boceprevir. While the pooled registration data suggest that telaprevir has higher rates of grade 3/4 anemia (hemoglobin levels <8.5 g/dL; 14% with telaprevir vs 6–10% with boceprevir), the boceprevir studies allowed the use of erythropoietin at the investigator’s discretion. While prospective, randomized, head-to-head trials assessing both frequency and severity of anemia are lacking, interim data from an ongoing French study (presented as an abstract at HepDART 2011) found on preliminary analysis that moderate, grade 2 anemia (hemoglobin level of 8–10 g/dL) occurred in 33% of telaprevir-treated patients and 31% of boceprevir-treated patients. Grade 3/4 anemia (hemoglobin level <8 g/dL) occurred in 13% of telaprevirtreated patients and 6% of boceprevir-treated patients. The transfusion rate was 18% for telaprevir-treated patients and 6% for boceprevir-treated patients. Overall, these findings correlate with clinicians’ anecdotal clinical experience, which shows significant anemia with both drugs.

G&H How frequently does anemia lead to either dose reduction or discontinuation of therapy?

SAH Dose reductions occur roughly twice as often when a protease inhibitor is added to the treatment regimen. According to the registration trial data, dose reductions occur in approximately 26% of patients treated with boceprevir.  Similarly, data from the telaprevir registration trials show that dose reductions occur in approximately 32% of patients. In terms of treatment discontinuation, data show that boceprevir-based therapy is discontinued in approximately 1% of patients, and telaprevir-based therapy is discontinued in 3–4% of patients. Again, both drugs show roughly similar rates of dose reductions and discontinuation.

G&H What are the clinical consequences of anemia?

SAH The presence of anemia does not negatively impact sustained virologic response (SVR) rates. However, it is well known that quality of life is certainly affected, which can lead to potential compliance or adherence issues. Recent data with the protease inhibitors suggest that clinicians can dose-reduce ribavirin fairly significantly in the setting of anemia and still achieve high SVR rates. Treatment discontinuation obviously has a more significant effect on clinical outcomes, but discontinuation is rare. Nonetheless, more data are needed to clearly show how quickly ribavirin dose reductions can occur (before virus negativity) and how long ribavirin can be stopped without affecting overall SVR rates. In the meantime, I advocate dose reduction instead of drug discontinuation for anemia, especially given that clinicians can probably get by with lower doses of ribavirin in the era of direct-acting antiviral drugs than they could when treating patients with pegylated interferon and ribavirin alone. If clinicians must discontinue ribavirin, they should do so for a short period of time (2–3 days) and then restart ribavirin at a lower dose.

In addition to necessitating dose reductions or discontinuations, anemia can significantly affect patients’ quality of life in terms of fatigue, inability to go to work and/or be productive at work, and difficulty in performing activities of daily living. As a result, compliance with therapy can become an issue. Thus, the effects of anemia extend beyond the possible impact on SVR rates to include compliance
and quality-of-life issues as well.

G&H Have any studies compared SVR rates in patients with and without anemia?

SAH Yes. There are 2 large studies in genotype 1 hepatitis C virus (HCV)-infected patients treated with pegylated interferon and ribavirin (IDEAL, n=3,070; CHARIOT, n=871) showing that patients who developed anemia (hemoglobin level <10 g/dL) were significantly more likely to obtain SVR than those without anemia. Post–hoc, retrospective studies with telaprevir and boceprevir have also been conducted, but to date, these results remain in abstract form. Data from the REALIZE trial and combined data from ADVANCE and ILLUMINATE (with telaprevir) demonstrate that anemia is not a significant predictor of SVR. However, a retrospective review of the SPRINT-2 and RESPOND-2 trials (with boceprevir) did find a positive association with anemia and SVR.

G&H Are there any factors that predict the likelihood of anemia in patients receiving protease inhibitor–based therapy?

SAH Patients who had significant anemia during prior treatment with pegylated interferon and ribavirin and are re-treated with boceprevir- or telaprevir-based triple therapy are likely to develop anemia again, and anemia may be more severe given the addition of the protease inhibitor. Retrospective data from the telaprevir registration trials show on multivariate analysis that older age, lower body mass index, lower baseline hemoglobin level, more advanced fibrosis, and genotype 1b HCV are all significantly associated with anemia. Retrospective data from the boceprevir registration trials show on multivariate analysis that baseline hemoglobin level, gender, age greater than 40 years, statin use, and race were associated with anemia.

G&H Can clinicians address some of these factors before starting treatment?

SAH Clinicians need to do due diligence and look at the patient’s past treatment. Was there significant anemia? Are patients starting out with lower hemoglobin levels? Are they cirrhotic? Are they older? Do they have any renal impairment issues? If any of these factors are identified ahead of time, then clinicians should be quicker to dose-reduce or add an agent like erythropoietin if hemoglobin levels begin to drop.

G&H How effective is erythropoietin for the management of anemia in patients who are receiving a protease inhibitor plus pegylated interferon and ribavirin?

SAH We lack good, clear-cut data regarding the effect of erythropoietin on SVR rates in patients treated with directacting antiviral drugs. Erythropoietin was not allowed in the telaprevir registration trials. In the boceprevir registration trials, erythropoietin was allowed at the discretion of the investigator, but these studies were not designed to evaluate the effect of erythropoietin on SVR rates. The results of a recently completed prospective trial assessing the benefits of concomitant erythropoietin use for anemia in boceprevir-based therapy are anxiously awaited.

Prior to the advent of direct-acting antiviral drugs, a prospective, randomized, placebo-controlled trial showed that the use of erythropoietin for anemia related to treatment with pegylated interferon and ribavirin resulted in maintenance of the ribavirin dose, stabilization of the hemoglobin decline, and improvement in quality of life compared to ribavirin dose reduction alone.

G&H When do you consider adding erythropoietin to a patient’s treatment regimen?

SAH This decision should be made at the discretion of the individual clinician, as there are no guidelines regarding the use of erythropoietin. If a patient experiences anemia, I personally prefer to try ribavirin dose reduction of 400–600 mg as a first-line measure, depending on the initial severity of the anemia. Then, if the hemoglobin level has not stabilized, I will add erythropoietin before further dose-reducing ribavirin or withholding ribavirin. While adding erythropoietin is not my first-line treatment for anemia, it is an option if a patient’s hemoglobin level is not stabilizing. Consideration can also be given to pegylated interferon dose reduction, as this may also help anemia. Data from the previously mentioned IDEAL trial show that with conventional pegylated interferon and ribavirin therapy, dose reductions from 1.5 mcg/kg/week to 1.0 mcg/kg/week did not adversely affect SVR.

G&H In which patients is erythropoietin contraindicated?

SAH The black box warning for erythropoietin states that this drug should not be used in patients with hemoglobin values greater than 12 g/dL. Thus, clinicians should not start erythropoietin until the patient’s hemoglobin level falls below 12 g/dL, and erythropoietin should be discontinued once the hemoglobin level rises back above 12 g/dL. Caution should be used when treating patients with endstage renal disease as well. Clinicians should also be aware of the relatively rare, but significant, complication of pure red cell aplasia that has been reported with the use of recombinant erythropoietin.

G&H What further research do you hope to see in this area over the next couple of years?

SAH Telaprevir and boceprevir, both of which are now approved by the US Food and Drug Administration, are the first direct-acting antiviral agents to come onto the market. Unfortunately, these drugs are associated with significant anemia; in general, patients who are receiving either of these drugs experience an additional hemoglobin decline of approximately 1 g/dL beyond the hemoglobin decline caused by pegylated interferon and ribavirin alone. The good news is that the second-generation direct-acting antiviral agents currently in development will probably cause less anemia than the 2 drugs that are currently available.

In addition to new drugs, we need further research regarding treatment of anemia in patients receiving telaprevir or boceprevir, including studies assessing how quickly we can dose-reduce ribavirin and by how much. The use of erythropoietin for anemia and its effect on SVR should be assessed. Finally, data suggest that polymorphisms in the inosine triphosphate pyrophosphatase (ITPA) gene may help to predict ribavirin-associated anemia during antiviral treatment, and further research is needed regarding the utility of this test. Should we be testing for this gene mutation in the same way that we now test for interleukin-28B (IL-28B) mutations prior to initiating antiviral therapy? More data are needed to determine whether this information would positively impact outcomes.

G&H How might such information help clinicians prevent treatment-induced anemia?

SAH If I had information suggesting that a patient was at increased risk for anemia, then I would probably check for anemia more frequently at the start of therapy. My preferred strategy—especially in patients who I feel are at risk for developing anemia—is to obtain complete blood counts at Week 1 and Week 2. If these tests show that the patient is doing well, then I may wait until Week 4 before performing follow-up testing. However, if testing at Week 1 and Week 2 shows that the patient’s hemoglobin level has dropped significantly, then I would adjust the ribavirin dose and obtain another complete blood count at Week 3. The key for treating anemia in the setting of HCV therapy is to address anemia very quickly, because it is much harder to bring hemoglobin levels back up after they have declined than it is to mitigate the rate of decline.

The opinion or assertions contained herein are the private views of the author and are not to be construed as official or reflecting the view of the US Department of the Army or the US Department of Defense.

Suggested Reading

Alavian SM, Tabatabaei SV, Behnava B. Impact of erythropoietin on sustained
virological response to peginterferon and ribavirin therapy for HCV infection: a
systematic review and meta-analysis. J Viral Hepat. 2012;19:88-93.

Mac Nicholas R, Norris S. Review article: optimizing SVR and management of the
haematological side effects of peginterferon/ribavirin antiviral therapy for HCV—the
role of epoetin, G-CSF and novel agents. Aliment Pharmacol Ther. 2010;31:929-937.

Nishimura T, Osaki R, Shioya M, et al. Polymorphism of the inosine triphosphate
pyrophosphatase gene predicts ribavirin-induced anemia in chronic hepatitis C
patients. Mol Med Report. 2012;5:517-520.

Jacobson IM, McHutchison JG, Dusheiko G, et al; ADVANCE Study Team.
Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J
Med. 2011;364:2405-2416.

Zeuzem S, Andreone P, Pol S, et al; REALIZE Study Team. Telaprevir for retreatment
of HCV infection. N Engl J Med. 2011;364:2417-2428.

Poordad F, McCone J Jr, Bacon BR, et al; SPRINT-2 Investigators. Boceprevir for
untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.

Bacon BR, Gordon SC, Lawitz E, et al; HCV RESPOND-2 Investigators.
Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J
Med. 2011;364:1207-1217.

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Provided by NATAP

at EASL next week there will be a presentation on TMC435 from this ASPIRE Study

STOCKHOLM, November 2, 2011 /PRNewswire/ --

ICAAC: TMC435 in combination with peginterferon and ribavirin for treatment of HCV genotype 1 infection: Week 24 interim analyses of Phase IIPILLAR and ASPIRE trials - (09/30/11)

TMC435-Based Therapy Significantly Improved Viral Cure Rates in Patients Who Failed Prior Treatment for Hepatitis C

- ASPIRE: All TMC435 subgroups achieved substantially higher viral cure rates (SVR24) compared with control group (pegylated interferon and ribavirin alone): 85% vs. 37% in prior relapsers, 75% vs. 9% in prior partial responders and 51% vs. 19% in prior null responders -

- Once daily TMC435 was generally safe and well tolerated at all doses and treatment durations -

Medivir AB (OMX: MVIR), a research-based speciality pharmaceutical company focused on infectious diseases, today announces final results from the ASPIRE study. This phase IIb study evaluated TMC435 once daily in addition to pegylated interferon (PegIFN) and ribavirin (RBV) in patients with genotype-1 chronic hepatitis C whose prior treatment with PegIFN and RBV was unsuccessful either because they relapsed, had a partial response or had a null response. Data from the ASPIRE study showed that patients in each of these subgroups who were treated with TMC435-based combination therapy achieved superior rates of sustained virologic response (viral cure) compared with those retreated with PegIFN and RBV alone.

Charlotte Edenius, Executive VP Research and Development, of Medivir commented, "We are extremely pleased with the final results from the ASPIRE study showing high viral cure rates and a favourable safety and tolerability profile in these difficult to treat genotype-1 hepatitis C patients whose prior treatment was unsuccessful. These results may provide new optimism for people who have failed on previous therapy, including those with advanced liver disease. We are highly committed to the broad and rapid development of TMC435 and global pivotal phase III clinical trials are currently well underway."

ASPIRE (C206) – Design

TMC435, a potent, once-daily, oral hepatitis C virus protease inhibitor, is being developed by Tibotec jointly with Medivir. The randomized, placebo-controlled, double-blind ASPIRE study evaluates the effect of TMC435 in combination with pegylated-interferon and ribavirin in 462 patients infected with genotype-1 hepatitis C virus who have failed prior treatment with PegIFN/RBV. The primary endpoint was proportion of patients with undetectable HCV RNA 24 weeks after the planned end of treatment (SVR24).

The study includes patients who have relapsed, achieved partial response, or achieved no response (null responders) to PegIFN/RBV treatment. 62 percent (287/462) of patients had advanced liver disease, periportal or septal fibrosis or cirrhosis (scarring of the liver) upon study entry (Metavir score F2-F4). Patients were equally randomized to one of seven different treatment arms, six TMC435 treatment arms and one placebo arm. TMC435 was administered once daily at a dose of either 100 mg or 150 mg given for either 12, 24, or 48 weeks in combination with 48 weeks of PegIFN/RBV. The results are based on the intent-to-treat (ITT), population which included all randomized patients who took at least one dose of the study medication.

Results – Efficacy

In this final analysis, all subgroups of treatment-experienced patients who failed previous PegIFN and RBV treatment, achieved substantially higher virologic response rates following treatment with TMC435-containing regimen at all doses and durations, compared with PegIFN and RBV alone.

Regardless of treatment duration all TMC435 treatment arms showed significantly improved effect on SVR24 versus PegIFN/RBV alone.

sus

q.d.: once daily; PR: pegIFNalpha-2A and ribavirin; EoT: End of Treatment, SVR24: patients with undetectable HCV RNA (<25 IU/mL Undetectable) 24 weeks after planned EoT. All TMC435 groups: p<0.001 vs placebo. Prior Relapser: undetectable HCV RNA at EoT and detectable within 24 weeks of follow-up Prior Partial Responders: more than 2 log reduction in HCV RNA at W12 but not achieving undetectable at EoT

Prior Null Responders: less than 2 log reduction in HCV RNA at W12 Results - Safety and Tolerability

TMC435 was generally safe and well tolerated and overall incidence of adverse events (AEs) was similar across treatment groups. Most of the AEs were grade 1 or 2 in severity. Serious AEs (SAEs) were reported in 6.1% subjects in the placebo and in 7.8% of the patients treated with TMC435. AEs leading to treatment discontinuation were reported in 4.5% of the placebo patients and in 7.8% of the TMC435 treated patients. Patients in the TMC435 ASPIRE treatment groups had overall longer treatment duration than patients in the placebo group due to a higher frequency of early discontinuation in the placebo group due to treatment failures (i.e. reaching viral stopping rules). The most common AEs during the treatment period were headache, fatigue, pruritus and influenza-like illness. Incidence was similar across treatment groups and the level of AEs and frequency were consistent with the prior phase IIb (PILLAR) study in treatment-naïve hepatitis C patients of TMC435.

In the safety analyses, special attention was given to the following AEs of interest: hepatobiliary AEs, pruritus, rash and anemia. Most AEs of interest were grade 1 or 2 in severity and infrequently led to treatment discontinuation. For each category of AEs of interest the incidence was similar for the TMC435 treatment arms and control arm.

Mild and reversible increases in bilirubin (total, direct and indirect) were observed in TMC435 dose groups with no differences between 100 mg and 150 mg. There were no meaningful differences between treatment groups for any of the other laboratory parameters. There were no clinically significant findings on vital signs. Mean alanine aminotransferase (ALT) levels decreased in all treatment groups.

DRAGON (C215) - Update on recently published results

The final data from the phase II Dragon study in Japan was recently published at the Japan Digestive Disease Week meeting, 20-23 October 2011 in Fukuoka, Japan. The DRAGON study is a phase II randomized, open-label, response-guided study to evaluate the efficacy, safety, and pharmacokinetics of TMC435 plus PegIFN/RBV in 92 Japanese treatment-naïve patients infected with HCV genotype-1.

Addition of once daily TMC435 (100 mg) to PegIFN/RBV increased the viral cure rate (SVR24) from 46% in the PegIFN/RBV only group to 82% (32/39) in the TMC435 100mg groups. In these groups, 87% of patients were eligible to complete all treatment at Week 24 if preset criteria on virologic response were met. TMC435 was generally safe and well tolerated with no apparent difference in the safety profile between TMC435 treatment groups and the control group (PegIFN/RBV only).

About TMC435

TMC435 is a highly potent and selective once-daily (q.d.) investigational drug that is being jointly developed by Tibotec Pharmaceuticals and Medivir to treat chronic hepatitis C virus infections.

TMC435 has received "Fast Track" designation by the U.S. Food and Drug

Administration ("FDA") for the treatment of chronic hepatitis C (CHC) genotype-1 infection. This is based on TMC435's potential to address unmet medical needs in the treatment of chronic HCV infection. TMC435 is currently being developed in three global phase III studies, QUEST-1 and QUEST-2 in treatment-naïve patients and PROMISE in patients who have relapsed after prior interferon-based treatment. In parallel with these trials, phase III studies for TMC435 in Japan, in both treatment naive and treatment experienced hepatitis C genotype-1 infected patients, are ongoing.

For additional information from these studies, please see http://www.medivir.com and http://www.clinicaltrials.gov

SOURCE Medivir

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New DAA FDA Guidance March 2012

Provided by NATAP

Reported by Jules Levin

presented by Russell Fleischer, PA-C, MPH, Senior Clinical Analyst, Division of Antiviral Products, US Food and Drug Administration, at the AASLD special topic meeting March 16-17 2012 in Atlanta

You have attended this conference or know already about the talk. I have attached the slide presentation but you can view the webcast & hear the talk on the AASLD website in the Liver Learning Portal.

from Jules: The language used in this presentation makes it clear in general guidance is fluid but the FDA also clearly steps into new territory with this new guidance saying they will consider historical controls for IFN-free regimens in phase 3, but didn't go beyond that. Inclusion of specifically mentioned special populations are encouraged, see slides. The biopsy discussion is interesting.

I have highlighted immediately below key points & slides presented, followed by the full slide presentation.

"I want to briefly update you on some of the activities we are engaged in around updating our HCV DAA guidance and what these changes may mean for the future development of DAA therapies. At the end I will discuss fast track as Ray asked me too, and I think there are some misconceptions about what this designation actually means."

Phase 3 trials should enroll adequate numbers of patients representative of the disease demographics: "we want to see" African-Americans, Latinos, compensated Cirrhotics, and "we want to open the door to 2 populations typically excluded from clinical trials": IVDU/opiate substitution.

For IFN-contraindicated we understand you cant randomize them to interferon "so if we have an IFN-free regimen thats going forward we are considering single arm historical control trials, if the phase 2 data is supportable of that approach, its probably only going to fly for really short duration regimens. This will work until 1 or 2 regimens are approved and then they will work as de facto standards of care, then we'll probably go with non-inferiority vs standard of care; another option would be an immediate vs deferred PBO controlled standard of care"

Continue to the Slide Presentation …

Article | 10 April 2012

For the treatment of hepatitis C virus (HCV), the majority of surveyed US physicians survey by advisory company Decision Resources who prescribe the Vertex (Nasdaq: VRTX) protease inhibitor Incivek (telaprevir) more often than the protease inhibitor Victrelis (boceprevir) from Merck & Co (NYSE: MRK) and Roche (ROG: SIX) perceive Incivek as offering a short, simple treatment duration and superior efficacy.

Similarly, surveyed managed care organizations’ (MCOs) pharmacy directors indicate that Incivek’s efficacy is the key driver of formulary inclusion. Physicians’ perception for sustained virologic response (SVR) as a key driver of prescribing for Incivek may suggest that emerging therapies with a higher SVR rate are likely to take patient share from Incivek unless they fall significantly short on other attributes such as safety or convenience.

The new US Physician & Payer Forum report, titled A New Era in the Treatment of Hepatitis C Virus: What Market Access Hurdles Are US Payers Erecting and How Are Physicians Responding? also finds that more surveyed physicians report that their HCV patients request treatment with Incivek over Victrelis. Although most surveyed physicians report that their HCV patients have not requested treatment with a specific protease inhibitor, requests for Incivek are more common than requests for Victrelis among physicians whose patients request a specific protease inhibitor.

“The greater interest among patients for Incivek suggests that information on its superior efficacy and/or dosing profile is well-known to the patient community and highlights the significant interest in new and emerging therapies for HCV,” said Decision Resources analyst Seamus Levine-Wilkinson.

Incivek and Victrelis increase treatment initiation

The report also finds that the availability of Incivek and Victrelis has increased the treatment initiation rate as nearly 80% of surveyed physicians indicate that they are treating more HCV patients since the launch of Incivek and Victrelis. Additionally, the pool of drug-treated HCV patients could continue to grow with the expected launch of new interferon-free therapies.

According to surveyed MCO pharmacy directors, efficacy is the key driver of Incivek’s formulary placement. The high efficacy of Incivek-based triple therapy is the most important driver of formulary inclusion and favorable tier placement of Incivek in commercial health plans. This support for Incivek’s efficacy likely influences pharmacy directors’ decisions to reimburse Incivek on the same tier as Victrelis, despite its higher cost. Efficacy is also the most important driver of formulary placement for Victrelis. The efficacy of Victrelis-based triple therapy is the most important driver of formulary inclusion and tier placement in commercial plans, although its influence is lower than for Incivek-based therapy.

Source

Also See: For the Treatment of Hepatitis C Virus, the Majority of Surveyed U.S. Physicians Who Prescribe Vertex’s Incivek More Often Than Merck/Roche’s Victrelis Perceive Incivek as Offering a Short, Simple and Highly Efficacious Treatment Option

Chemo Brain: It is Real

Those of us that have done treatment for Hepatitis C can so relate to this …


April 09, 2012

By Terri Ades, DNP, FNP-BC, AOCN

Recently a colleague at work who had just returned from a getting a haircut mentioned to me that his hairdresser, who has lung cancer, was upset because her husband was very worried about her. The hairdresser explained that she had started having some memory problems - couldn't remember what she did yesterday or couldn't remember people's names. And she had started to tell her husband something and stopped in the middle of her story - not remembering what to say next. She too acknowledged being a little concerned and was seeing her doctor in 3 days, but she didn't know how to help her husband until then. I asked if she was receiving chemotherapy and was told yes, so I explained that she might have "chemo brain."

We've known for some time that radiation therapy to the brain can cause problems with thinking and memory. Now, we are learning that chemotherapy is linked to some of the same kinds of problems. Research has shown that some chemotherapy agents can cause certain kinds of changes in the brain. Though the brain usually recovers over time, the sometimes vague yet distressing mental changes cancer patients notice are real, not imagined. These changes can make people unable to go back to their school, work, or social activities, or make it so that it takes a lot of mental effort to do so. These changes affect everyday life for many people receiving cancer treatment.

Patients report the following symptoms:

  • Short-term memory lapse -- forgetting things that they usually have no trouble recalling
  • Trouble concentrating -- can't focus on what they're doing, have a short attention span, may "space out"
  • Trouble with word-finding, such as remembering names, not completing sentences, or not being able to think of a word
  • Trouble multi-tasking, like answering the phone while cooking, without losing track of one task
  • Taking longer to finish things-- slower thinking and processing

Doctors and researchers refer to these symptoms as a "mild cognitive impairment," but they're commonly called "chemo brain." For most people, chemo brain happens quickly and only lasts a short time. Others have long-term mental changes. Usually the changes that patients notice are very subtle, and others around them may not even notice any changes at all. Still, the people who are having problems are well aware of the differences in their thinking. Many people do not tell their cancer care team about this problem until it affects their everyday life.


What causes chemo brain?

Studies suggest that there may be more than one cause of chemo brain, especially for the short-term symptoms. Some people with cancer have very real brain problems even though they have not had chemotherapy. Still others notice problems when getting hormone treatments, such as estrogen blockers or androgen deprivation therapy. For some, problems start after surgery.

Along with chemotherapy, other health problems that might cause or worsen brain function include: the cancer itself; other drugs; patient age; stress; low blood counts; sleep problems; infection; depression; fatigue; hormone changes or hormone treatments; other illnesses, such as diabetes or high blood pressure; nutritional deficiencies; and anxiety or other emotional distress.

Most of these cause short-term problems, and get better as the underlying problem is treated or goes away. A few factors, such as depression, can cause long-lasting brain problems unless the cause is treated.


What can patients do about it?

So far, there is no way to prevent chemo brain while you are getting cancer treatment. For some people, treating their cancer will mean trouble with thinking, memory, planning, and word finding. If you are having symptoms, the first step is to discuss them with your cancer care team. They will consider what the underlying cause is, then help you identify some management strategies.
The following are steps that some patients have found helpful in managing their day-to-day living.

  • Write things down. Keep track of appointments and schedules, to-do lists, important dates, phone numbers and addresses.
  • Exercise your brain. Take a class, do word puzzles, or learn to do something new.
  • Exercise your body. Regular physical activity is good for your body; it improves your mood, makes you feel more alert, and helps you feel less tired.
  • Get enough rest and sleep.
  • Eat your veggies. Studies have shown that eating more vegetables can help you keep up your brain power.
  • Set up and follow routines. Put the things you often lose in the same place each time you're done with them. Try to keep the same daily schedule.
  • Give yourself permission to focus on one thing at a time.
  • Choose only those activities that are important to you and allow yourself plenty of time to complete tasks.
  • Consider use of relaxation techniques such as yoga or meditation.
  • Track your memory problems. Keep a diary of when you notice problems and the events that are going on at the time. Medicines taken, time of day, and where you are may help you figure out what affects your memory. Don't plan important tasks or events when your memory problems are worse.
  • Do not criticize yourself for not being able to remember. Accepting the problem will help you deal with it. Patients say that being able to laugh about things you can't control can help you cope. And remember, you probably notice your problems much more than others do.

Also, be sure to tell your family and friends what is going on with you. They will be relieved and will worry less. You are not crazy and you area not losing your mind. Chemo brain is real.


More research is needed

More research is needed so we can better understand chemo brain, but it is not easy to study. For example, researchers may use different tests to measure the problems with thinking and memory, so the results may not compare well with each other. Some people report changes that are so mild that their brain tests look normal and doctors don't have a good way to measure the changes.

There are also differences in when certain kinds of brain problems happen. Some researchers have tested brain function a few weeks after treatment, others months or even years later. If the problem only lasts a few weeks with no long-term changes, late testing can miss it. If the changes last more than a year but the testing stops after 6 months, no one knows how long they last. Another timing problem in studying chemo brain is that most studies didn't test the patients before treatment to compare to results after treatment.

In studies that did test before treatment, some people were seen to have brain function problems before treatment was even started. So it's possible that the cancer itself causes some of the problems, or that some other related problem (like anxiety about having cancer) caused brain function to decline. Studies are needed that test people before the treatment and then follow up to look for changes over time.

So, my colleague quickly called his hairdresser and said, "I want you to talk to this oncology nurse practitioner about your symptoms." And she agreed. I explained that her symptoms sounded like chemo brain. I could hear the relief in her voice. Of course she was planning to tell her doctor about her symptoms, but she was going home to tell her husband not to worry!

For more information about chemo brain and other chemotherapy side effects, click here.

Dr. Ades is director of cancer information for the American Cancer Society.

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Hep C anti-virals not as effective as trials suggest

Gastroenterology Update Newsletter

April 11, 2012

Kate Aubusson

Doctors cannot assume results from clinical trials are transferable to their clinical practice, conclude the authors of a study showing hepatatis C treatments in some patients are less effective than suggested by trial data.

The retrospective study compared the results of pegylated interferon and ribavirin therapy in pharmaceutical trials to those of over 400 patients treated in a tertiary hospital and found that though results for patients with genotypes 1 and 2 infections were comparable, the results for genotype 3 patients were “inferior” in a clinical setting.

Of the 187 genotype 3 patients included in the hospital cohort 72% achieve a sustained virological response (SVR) compared to 76-84% in pharmaceutical trials, the researchers reported in Internal Medicine Journal.

The authors from Flinders Medical Centre in Adelaide said the reason for the genotype 3 group’s poorer performance in the clinical setting was unclear, considering the SVR results for genotype 1 and 2 were within the range of trial results at 55% and 82% respectively.

But overall the authors suggested the differences in outcomes between pharmaceutical trials and day-to-day practice “are likely to relate to differences in treatment and patient support, and inclusion of subjects who may not meet trial inclusion criteria”.

The findings are particularly relevant as dual anti-viral therapy with pegylated interferon and ribavirin begins to be phased out and replaced by more complicated triple therapy regimens, they said.

“Whether impressive results from pharmaceutical trials containing direct anti-virals regimens can be replicated in real life situations will be important to confirm.”

The authors advised clinicians to be aware of outcomes in their own practice and provide patients with accurate local SVR data.

Internal Medicine Journal,
Online First April 2012. DOI:
10.1111/j.1445-5994.2012.02798.x

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