Claude Monet Reading A Newspaperby Pierre Auguste Renoir
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The American Association for the Study of Liver Diseases November 2011 Annual Meeting
This video should be a resource for patients considering HCV therapy, as well as those already on treatment. Family members and caregivers should also be familiar with its content. Of course, this video is a tool, and does not replace seeing a mental health professional. Patients of mine will see Dr Pate as needed. For those elsewhere, speak with your treating physician, as well as your family physician, and investigate prior to starting treatment what resources are available to you in the event psychiatric side effects develop.
AASLD: Milk Thistle No Help in Chronic HCV
By Charles Bankhead, Staff Writer, MedPage Today
Published: November 14, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.
Action Points
* Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
* Explain that neither high-dose or usual-dose milk thistle did not improve serum alanine aminotransferase levels in patients with previously treated chronic HCV infection compared with placebo in a randomized, controlled trial.
* Note that HCV RNA and quality of life values also did not change in those receiving the milk thistle in a standardized preparation of 15 pills per day.
SAN FRANCISCO -- A botanical agent used in the treatment of liver disorders had no detectable effect on hepatitis C virus (HCV) disease activity in comparison with placebo in patients with previously treated chronic disease, results of a randomized trial showed.
Patients treated for six months with either of two doses of silymarin had little change in levels of the liver enzyme alanine transaminase (ALT). About 4% of patients in each silymarin arm and in the placebo group met the primary endpoint of a decline in ALT to less then 45 IU or at least a 50% decline from baseline.
"Similarly, symptom scores and quality of life measures were unchanged during silymarin treatment," Michael W. Fried, MD, of the University of North Carolina in Chapel Hill, reported here at the American Association for the Study of Liver Diseases meeting.
The trial was perhaps the first to use a single, well-described silymarin preparation, and the doses employed in the study were five to seven times higher than customary doses, he added.
Silymarin is an extract of milk thistle and has long been used as a treatment for various types of liver disorders. A mixture of flavonolignans, silymarin has demonstrated anti-inflammatory and immunodulatory properties in vitro, as well as activity against the HCV core and virus-associated gene expression.
The substance has been evaluated in clinical trials as a therapeutic aid for cirrhosis, alcoholic liver disease, and viral hepatitis. However, the results have been inconsistent.
"Previous studies have been confounded by a lack of well-defined efficacy endpoints, inclusion of heterogeneous populations of patients with liver disease, and use of nonstandardized silymarin preparations," said Fried.
To address some of the shortcomings of previous clinical studies, the investigators designed a trial to evaluate silymarin as a potential aid in the treatment of chronic HCV that had not responded to interferon-based therapy.
All of the 154 patients enrolled at four centers in the U.S. had a history of treatment with interferon-based therapy and had not achieved a sustained virologic response. The patients had quantifiable HCV RNA and a serum ALT more then 65 IU.
The silymarin preparation used for the trial is produced in the Netherlands under the brand name Legalon 140 and is approved as a prescription drug in some European and Asian countries. The customary dose is 140 mg three times a day.
Eligible patients were randomized to one of two doses of silymarin (420 or 700 mg) or placebo. Patients in the high-dose silymarin arm took five capsules of the botanical agent three times daily. Patients randomized to the standard dose took three silymarin capsules and two placebo capsules three times each day, and patients in the placebo arm took five matching capsules three times daily.
The high-dose arm was based on results from a phase I dose-finding trial "in order to provide the highest likelihood of finding a therapeutic benefit," said Fried.
The primary endpoint, measured after 24 weeks, was a decline in serum ALT to less then 45 IU (the upper limit of normal) or a decline of at least 50% from baseline and less then 65 IU (1.5 times the upper limit of normal).
The patients were randomized to the three treatment arms. The three groups did not differ with respect to baseline demographic and clinical characteristics. Median age was 55, about 70% were white, about 90% had HCV genotype 1, about a fourth of the patients had evidence of cirrhosis, and 40% to 45% had a history of milk thistle use.
Adherence was good, said Fried, as about 90% of the study participants consumed more than 80% of their medication doses.
After six months, one person in the placebo group had a serum ALT less then 45 IU, as did two patients in each of the silymarin arms. Additionally, two patients in the placebo and high-dose silymarin groups had at least a 50% decline in baseline ALT to less then 65 IU, as did one patient in the 420-mg silymarin arm.
The proportion of patients who met either definition of the primary endpoint was 3.8% (two of 52) in the placebo group, 4% (two of 50) in the 420-mg silymarin arm, and 3.8% (two of 52) in the high-dose silymarin arm.
The three groups also did not differ significantly with respect to the mean change in ALT, change in HCV RNA, or scores on a battery of quality-of-life instruments. A graph of serum ALT levels throughout the six months showed virtually superimposable lines for the three groups.
The placebo and silymarin groups also did not differ significantly in their adverse-event profiles. The most common types of adverse events were gastrointestinal, musculoskeletal, dermatologic, infection, and physical injury. Six patients in the 420-mg silymarin arm and five in the 700-mg arm had serious adverse events, compared with one in the placebo group.
During the discussion that followed the presentation, Fried expressed doubt that using even higher doses of silymarin might lead to better results, as suggested by a member of the audience.
AASLD president T. Jake Liang, MD, said the study is informative because the results showed not only that silymarin performed no better than placebo in a well-controlled clinical trial but also that the substance is not harmful for people who take it for liver conditions.
Fried disclosed relationships with Genentech, Tibotec, Vertex, Merck, Abbott, Pharmasset, Anadys, Bristol-Myers Squibb, and GlaxoSmithKline.
Primary source: American Association for the Study of Liver Diseases
Source reference:
Fried MW, et al "A randomized, placebo-controlled trial of oral silymarin (milk thistle) for chronic hepatitis C: final results of the SYNCH multicenter study" AASLD 2011; Abstract 228.
New: Testing Postitive Now What Brochure
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DEB025 (Alisporivir)
From PLoS ONE: an inclusive, peer-reviewed, open-access resource from the PUBLIC
LIBRARY OF SCIENCE
Abstract
DEB025/Debio 025 (Alisporivir) is a cyclophilin (Cyp)-binding molecule with potent anti-hepatitis C virus (HCV) activity both in vitro and in vivo. It is currently being evaluated in phase II clinical trials. DEB025 binds to CypA, a peptidyl-prolyl cis-trans isomerase which is a crucial cofactor for HCV replication.
Here we report that it was very difficult to select resistant replicons (genotype 1b) to DEB025, requiring an average of 20 weeks (four independent experiments), compared to the typically <2 weeks with protease or polymerase inhibitors. This indicates a high genetic barrier to resistance for DEB025. Mutation D320E in NS5A was the only mutation consistently selected in the replicon genome. This mutation alone conferred a low-level (3.9-fold) resistance. Replacing the NS5A gene (but not the NS5B gene) from the wild type (WT) genome with the corresponding sequence from the DEB025res replicon resulted in transfer of resistance. Cross-resistance with cyclosporine A (CsA) was observed, whereas NS3 protease and NS5B polymerase inhibitors retained WT-activity against DEB025res replicons. Unlike WT, DEB025res replicon replicated efficiently in CypA knock down cells. However, DEB025 disrupted the interaction between CypA and NS5A regardless of whether the NS5A protein was derived from WT or DEB025res replicon. NMR titration experiments with peptides derived from the WT or the DEB025res domain II of NS5A corroborated this observation in a quantitative manner. Interestingly, comparative NMR studies on two 20-mer NS5A peptides that contain D320 or E320 revealed a shift in population between the major and minor conformers.
These data suggest that D320E conferred low-level resistance to DEB025 probably by reducing the need for CypA-dependent isomerisation of NS5A. Prolonged DEB025 treatment and multiple genotypic changes may be necessary to generate significant resistance to DEB025, underlying the high barrier to resistance.
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AASLD-Novartis’ alisporivir may become first interferon-free oral for hepatitis C G2/G3
The clear conclusion from a clinical trial of alisporivir (DEB025, from Swiss drug major Novartis , an oral host-targeting cyclophilin inhibitor, is that treatment based on it may be an effective, interferon (IFN)-free alternative for individuals with genotype 2 or 3 (G2/G3) hepatitis C virus (HCV) infections. The finding was presented by Jean-Michel Pawlotsky, a professor at the Henri Mondor Hospital, University of Paris-Est, Creteil, France, at a late-breaking poster session on November 7, 2011 at the 62nd annual meeting of the American Association for the Study of Liver Diseases (AASLD) held last week in San Francisco.
Novartis in-licensed DEB025 from Debiopharm, an independent biopharmaceuticals company based in Switzerland, under an agreement which gives Novartis exclusive worldwide development, manufacturing and marketing rights (excluding Japan; The Pharma Letter February 9, 2010).
IFN therapy is associated with significant adverse events, including flu-like symptoms, fatigue and nausea, all of which can significantly impact treatment adherence, and therefore also response rates and disease control. HCV G2/G3 represents the second most prevalent variant of HCV infection. While an effective and well-tolerated oral IFN-free HCV treatment would likely be widely embraced, because registrations trials are not yet completed, investigators and Novartis representatives were unwilling to speculate on the impact of an ultimate alisporivir approval.
Attraction of an oral agent
Dr Pawlotsky noted that alisporivir is attractive as an HCV treatment because it is an oral agent, it has potent activity across the HCV genotypes, and it has demonstrated a high barrier to viral resistance.
The international, multicenter, open-label study led by Dr Pawlotsky and colleagues included 334 G2/3 patients (ratio 3:7) who had not been treated previously for HCV infection. They were randomized to five treatment arms:
• alisporivir 1,000mg daily monotherapy (ALV1000) (n=82),
• alisporivir 600mg daily plus ribavirin (R) (ALV600R) ( n=84],
• alisporivir 800mg daily plus R (ALV800R) (n=94),
• alisporivir 600mg daily plus pegylated interferon (P) (ALV+P) (n=39), or
• P plus R (P+R) (n=35).
In week one, all alisporivir-treated patients received ALV 600mg twice daily. Patients receiving alisporivir as IFN-free treatment who achieved undetectable HCVRNA (less then 25 IU/mL) at week four remained on initial treatment, while those with detectable HCVRNA had add-on IFN and continued with ALV+PR triple therapy from week six to week 24.
From week four to six, the proportion of patients with undetectable HCV RNA with alisporivir-based, IFN-free therapy increased further to 32%, 49% and 46% in the AlV1000, ALV600R and ALV800R groups, respectively.
The proportion of patients with undetectable HCV-RNA levels was higher with alisporivir plus R than with alisporivir monotherapy. The RVR rate was about 60% higher for patients with lower baseline HCV RNA (less then 800,000 IU/mL) than for the overall group. However, for those alisporivir patients who did not achieve RVR by week four, add-on IFN as triple therapy (alisporivir 600mg daily plus PR plus IFN) from week six resulted in rapid HCV clearance with more than 90% of patients having undetectable HCV-RNA levels at week 12.
Fewer adverse events
Markedly lower rates of flu-like symptoms (fatigue, pyrexia, myalgia and arthralgia) were reported for alisporivir-based IFN-free as compared with IFN-containing treatment. For example, fatigue, headache and pyrexia were reported at percent rates of around13, 12 and 3, respectively, in the IFN-free arms and at about 27,27 and 23, respectively, in the add-on IFN arms. Overall, fewer adverse events were reported in the alisporivir arm of the trial. Transient increase in serum bilirubin (more then 5xULN) was observed in five (2%) of alisporivir-treated patients. Serum ALT levels remained normal. Grade 1&2 anemia reported in 19% to 27% of patients receiving alisporivir-regimens was attributable to ribavirin (anemia occurred in 27 percent of the standard of care PR arm). There were no reports of grade 3&4 anemia. Also, neutropenia, found in 17% of patients in the PR arm, was not observed in the alisporivir-based IFN-free arms. Only two patients discontinued treatment on account of adverse events.
Dr Pawlotsky commented: “Alisporivir once daily shows promise to become the first interferon-free oral treatment for a substantial proportion of treatment-naïve HCV G2/G3 patients.”
HVC affects more than 170 million people worldwide. Alisporivir, with potential to address an unmet need in this population, was been granted fast track review by the US Food and Drug Administration.
An ongoing pivotal Phase III study with DEB025 is evaluating the efficacy and safety of DEB025 plus interferon and ribavirin in previously untreated HCV genotype 1 patients.
This article explores some of the issues in the history and pathophysiology of chronic hepatitis C
Discussion Only
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Viral factors have usually been considered to have limited influence on liver FPR in chronically infected HCV patients.[29] However, recent studies highlighted a possible association between viral genotypes and rapid fibrosis progression. By pooling results from several, often small-sized studies, this meta-analysis provides a comprehensive summary of the published literature on the topic as well as new insights into the natural history of chronic HCV infection. The pooled analyses of eight single-biopsy studies clearly confirmed a significantly faster progression for genotype 3 patients compared with the other genotypes. Among them, five showed a significantly faster fibrosis progression or a clear trend towards faster progression for genotype 3-infected patients compared with others.[5–7,16,22] The failure of some studies to detect a significant effect for viral genotype 3 probably results from their insufficient sample size (i.e. 342 cases and 684 controls are necessary for 80% power to detect an OR of 1.5 for viral genotype 3 on fibrosis progression, considering a 30% prevalence of this genotype). Despite a much smaller observation time, the pooled analysis of eight paired biopsies studies showed a trend towards faster progression for genotype 3-infected compared with genotype non-3-infected patients.
A previous study assessing stage-specific FPR using a Markov model suggested that viral genotype 1 (compared with other genotypes) may influence fibrosis progression, but the estimation was performed using a meta-regression.[30] It is known that such ecological associations may lead to incorrect estimates of the relation for individual patients.
The association of viral genotype 3 with FPR may have important practical implications. It has been reported that the uptake of antiviral therapy for hepatitis C has been declining during recent years.[31] Apart from poor rate of diagnosis and lack of referral, two major factors may account for this trend: the widespread perception on the supposedly slow average progression rate of hepatitis C, coupled with the huge expectations surrounding novel, more effective direct antiviral agents (DAA), to be first marketed in 2011–2012. Genotype 3-infected patients should be aware of a potentially faster progression rate and may benefit from individualized counselling, with particular attention given to the controllable factors, such as alcohol consumption and overweight.[32] While therapy with peginterferon alpha and ribavirin usually achieves 70–80% of sustained viral response among patients infected with HCV genotype 3, certain subgroups of patients still have high relapse rates, such as those with elevated baseline viral load (>800 000 copies/mL,[33,34]) and advanced fibrosis.[32] Patients with chronic hepatitis C may be deferred from current treatment regimens just because more potent DAA will be licensed in the near future.[35] However, this 'warehousing' attitude may not be justified in infections with genotype 3, given that the serine protease inhibitors, such as telaprevir, have very limited activity against genotype 3.[36] DAAs with significant activity against genotype 3, such as the nucleoside RNA polymerase inhibitor R7128[37] or the cyclophilin-binding molecule Debio 025,[38] are far from completing clinical development. These considerations argue against the indiscriminate deferral from antiviral therapy in patients infected with genotype 3.
Multiple reasons may explain why paired biopsies studies did not show a significant effect of genotype 3. First, confounding by indication is likely to be a major problem in paired biopsies studies, as only selected patients undergo a second biopsy (e.g. those with multiple comorbidities and potentially rapidly evolving liver disease). Second, paired biopsies studies have a smaller sample size than single-biopsy studies. Out of eight studies, none included more than 30 genotype 3 patients, and four included less then 7 genotype 3 patients, resulting in low power to detect a given ES. Third, paired biopsies studies have a much smaller observation time than single-biopsy studies (~5 years between 2 biopsies compared with ~13 years from the infection date to the first biopsy, Fig. S3). This short duration may not be sufficient to detect genotype-specific differences in terms of FPRs. Fourth, paired biopsies studies have used arbitrary cut-offs for dichotomizing the outcome into progression vs nonprogression, for instance a worsening of the score by one or several units[13–15,17,18,20,23] or reaching a specific fibrosis stage at the second biopsy.[19] This method results in more information loss if one considers that the process of fibrosis is continuous. Finally, given that FPRs are not constant over time, paired biopsies studies may have included patients when the progression rate is the slowest (e.g. transition from Metavir scores F1–F2[30] or F2–F3[7]), making it even more difficult to detect genotype-specific differences (Fig. S2).
As in many systematic reviews, the limitation of this study results from the limitation of the original studies themselves. Those include the inability to precisely determine the date of infection, the variability in the assessment of fibrosis staging, the nonlinearity of fibrosis progression over time, the failure to account for multiple risk factors. However, several studies addressed these issues. In three studies, the role of viral genotype 3 in fibrosis progression was confirmed in multivariate analyses, accounting for different covariates such as age, alcohol consumption and steatosis.[5–7] In one of them, the authors suggested that cannabis use, which may be more prevalent among genotype 3-infected patient, may have been a confounding factor for the role of genotype 3. However, this study clearly identified cannabis use, genotype 3, age at infection, alcohol intake and steatosis all as independent risk factors for rapid fibrosis progression (greater then 0.74 U/year) in a stepwise logistic regression model of 267 patients.[5] In another study, the association of genotype 3 with faster progression remained significant among patients infected by blood transfusion (for whom the date of infection is certain), among different age groups, or among different periods of infection, and when using different methods to assess the progression rate.[7]
Owing to our stringent selection criteria, the number of studies included in the meta-analysis is relatively small. Therefore, it was not possible to perform a meta-regression analysis and explore the role of potential confounders. We could not include a large confirmatory study (N = 327, N genotype 3 = 80), showing that patients infected with HCV genotype 3 had shorter time to infection than others, because it did not provide FPR rates.[39]
This study provides new insight into the natural history of HCV infection. The evidence for a role of genotype 3 in fibrosis progression may have important implications for the management of patients infected with this genotype.
Related Sept 2011-HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis
About eltrombopag (PROMACTA®/Revolade®)
Hepatitis B
Successful treatment of activated occult hepatitis B in a non-responder chronic hepatitis C patient
Virology Journal 2011, 8:518 doi:10.1186/1743-422X-8-518
Published: 14 November 2011Abstract (provisional)
Click Here For Full Text PDF
We reported a 23 years old male with chronic hepatitis C virus infection, discontinued from pegylated interferon/ribavirin combination therapy due to a lack of early virological response. He has developed activation of occult hepatitis B virus that was successfully treated by a one year of lamivudine therapy.
Liver Cancer
Liver Cancer: Increasing Incidence, But Greater Therapeutic Options
Although hepatocellular carcinoma (HCC) does not garner the type of publicity breast cancer and colon cancer receive, it clearly remains a major cause of cancer mortality.
In the United States, the incidence of liver cancer remains the fifth and ninth leading cause of cancer deaths in men and women with an estimated 13,260 male and 6,330 female deaths in 2011. In contrast to the incidences of colon, lung and breast cancer, which are decreasing, the incidence of liver cancer is increasing.1
Studies (Davila et al, Gastroenterology, 2004) indicate this is in part due to the large number of people infected with viral hepatitis. Because of the latency between viral infection, cirrhosis, and the development of cancer, it has been projected that the number of hepatitis C related liver cancer cases will continue to rise and potentially double over the next 10-20 years (reviewed by El-Serag, Hepatology 2002).
The American Association for the Advancement of Liver Disease (AASLD) has developed recommendations for screening populations at risk. For chronic hepatitis B carriers, the guidelines recommend screening Asian males forty years of age or older, Asian females 50 years of age or older, all hepatitis B carriers with cirrhosis, all hepatitis B carriers with a family history of HCC and African hepatitis B carriers older than 20. Screening should also be offered to patients with cirrhosis related to hepatitis C, alcohol, hemochromatosis, and primary biliary cirrhosis.
Because patients who develop hepatocellular cancer often have cirrhosis as well, treatment algorithms and tumor staging systems have been developed to try to incorporate the degree of hepatic dysfunction in the recommendations for treatment.
For example, the treatment recommendation for a patient with a small tumor but with advanced cirrhosis may be different than a patient with the same size tumor but much better liver function and reserve. Multiple staging systems have been described to try to determine the best way to segregate patients to the appropriate treatment algorithm. One current commonly used algorithm is the Barcelona Clinic Liver Cancer (BCLC) staging classification. This staging system, Fig 1, takes into account underlying liver function as represented by the patient’s Child-Pugh-Turcotte score, as well as, tumor size, vascular involvement, the presence of extrahepatic disease and the patient’s performance status.
Multiple tools have been added to the armamentarium for the treatment of hepatocellular cancers. These can be separated into three categories: surgical, medical and radiological. Surgical options include resection, ablation and transplantation.
In a patient with HCC and no underlying cirrhosis, the goal should be resection if possible. In a study by Llovet et al. (Hepatology 1999), excellent five year survival rates were reported (74%) for patients with a normal bilirubin and no portal hypertension who were treated with resection. Arii et al. (Hepatology 2000) reported similar survival rates for 1,318 patients who underwent resection for the treatment of small (< 2 cm) hepatocellular cancers.
Most patients with hepatocellular cancers and early stage tumors are not candidates for resection based on poor underlying liver function and inadequate liver reserve. Based on a publication by Mazzaferro et al. (NEJM 1996) the United Network for Organ Sharing, UNOS, currently gives special consideration to patients who have a liver cancer that is less than 5 cm in size or have three or fewer tumors, no individual tumor larger than 3 cm. These criteria have become known as the Milan criteria. Patients that satisfy these requirements can be placed on the transplant list and are awarded enough points that they can often be transplanted relatively quickly. In Ohio they often can be transplanted within 3-6 months. Transplant recipients who met Milan criteria were found to have a 75% four year survival.
Ablation may be a possible treatment for patients with small tumors, < 3 cm, with hepatic dysfunction severe enough to preclude them from resection. This treatment modality employs either cold (cryoablation) or heat (radiofrequency/microwave) to destroy tumors. Interventional radiologists and radiation oncologist also have effective treatments which can be offered to appropriate candidates.
Within the last several years, sorafenib, a multiple kinase inhibitor, was FDA approved for the treatment of unresectable hepatocellular carcinoma. In a randomized control trial, sorafenib was shown to increase survival over best supportive care.
With so many options now available for the treatment of hepatocellular carcinoma, trials are now underway to evaluate the effect of combining various treatments to obtain better long term survival. In addition, efforts are underway to educate the general population on the importance of screening high risk groups at regular intervals. By finding cancers earlier and having multiple tools to treat patients, new found hope has been given to curing this disease.
Dr. Christopher Siegel is an associate professor of Surgery, Case Western Reserve University, and Surgical Director, Liver Center of Excellence, Digestive Health Institute, University Hospitals
Case Medical Center.
Reference
1. Siegel, R., Ward, E., Brawley, O., Jemal A., Cancer Statistics, 2011, CA Cancer J Clin 2011;61:212-236
MD News November/December 2011, Cleveland/Akron/Canton
Biosimilars
The primary concern for the FDA is how to ensure that a biosimilar is the same as its original biologic.
With biosimilars this is not always the case. That's because biologics are more complex structures that are much more difficult to replicate. An error in reproduction could cause unanticipated or harmful side effects
Right now, no biosimilar exists on the U.S. market; because of their complexity, they weren't included in the Hatch-Waxman legislation that set the regulatory framework for other generic drugs.
This is a tremendously important task. In order to ensure the safety of biosimilar drugs for patients, the FDA must:
Require clinical trials or other appropriate clinical testing before the approval of biosimilars
Ensure robust pharmacovigilance, the surveillance of a drug's performance, including adverse reactions, after it's been released for marketing. Of primary importance is the creation of a traceability system that includes distinctive labeling, product tracking codes, and a way to report adverse reactions
Guarantee that patients and their doctors have the ability to decide treatment by ensuring a treatment plan is not altered by a pharmacist without the consent of the physician and patient
Including these requirements would assure patients and their families that the FDA is set on striking the right balance between cost effectiveness and patient safety.
Like countless medical advances in the past, biologics and biosimilars could revolutionize the way the U.S. treats some of the most painful, most deadly diseases. But like the advances that came before them, these new treatments must undergo a thorough evaluation process before their approval.
Thanks to numerous scandals, the FDA is under mounting pressure to step up its oversight of drug development and manufacturing. But what do the metrics look like? Well, the agency has now released numbers showing its efforts to inspect and audit facilities that are involved in drug development specifically, such as clinical trial investigators and institutional review boards.
From Nov 6 @ shearlingsplowed.blogspot.com
Whitehouse Station is hoping to make a splash at the 62nd Annual Meeting of the American Association for the Study of Liver Diseases, in San Francisco, this coming week -- with some putative Victrelis® (boceprevir) Hep C news.
The difficulty -- for Merck's marketing mavens -- is that in essentially analogous/head to head interim trial outcomes, Vertex's Incivek® (telaprevir) comes out WAY ahead, in treating Hep C non-responders. And the IMS data shows that prescribing physicians are now well-aware of the vastly differential efficacy, betwen the two competitors -- thus:
. . . .Vertex -- Incivek -- Study 111 (ILLUMINATE)
This randomized, open-label trial was designed to compare SVR rates in 540 subjects achieving eRVR who were treated with Incivek for 12 weeks in combination with Peg-IFN-alfa-2a/RBV for either 24 weeks (T12/PR24 regimen) or 48 weeks (T12/PR48 regimen). The SVR rate for all subjects enrolled in the trial was 74%. A total of 352 (65%) subjects achieved eRVR and of those 322 (60%) were randomized to 24 weeks (T12/PR24, n=162) or 48 weeks (T12/PR48, n=160) of treatment. The SVR rates were similar at 92% (T12/PR24) and 90% (T12/PR48), respectively. Sixty-one (11%) of subjects had cirrhosis at baseline. Among these subjects, 30 (49%) achieved an eRVR: 18 were randomized to T12/PR24 and 12 to T12/PR48. The SVR rates were 67% (12/18) for the T12/PR24 group and 92% (11/12) for the T12/PR48 group. African Americans comprised 14% of study subjects. . . .
[And, the roughly-analogous Merck Victrelis interim results, trumpeted Friday:
In the interim results of the PROVIDE study, approximately one-third of the patients who had a null response to prior peginterferon alfa and ribavirin therapy and failed treatment were able to achieve a sustained virologic response when retreated with VICTRELIS in combination therapy,” said John M. Vierling, M.D., F.A.C.P, professor of Medicine and Surgery at the Baylor College of Medicine in Houston, Texas, director of Baylor Liver Health and Chief of Hepatology, who presented the PROVIDE data. . . .
FYI
Boehringer says about 260 deaths related to Pradaxa
Nov 12 (Reuters) - Boehringer Ingelheim said that 260 cases of fatal bleeding have been linked to its new stroke prevention pill Pradaxa so far, adding that the risk of death was still below the rate that emerged in the clinical trial that led to the drug's approval.
In early November, the German drugmaker had said that 50 reported deaths were a "reasonable order of magnitude".
The company on Saturday confirmed in a statement the new global number more than five times higher than the previous one, initially reported by magazines Der Spiegel and Die Zeit.
Like other anti-blood-clotting treatments, Pradaxa's benefit of cutting the rate of fatal or debilitating strokes comes at the risk of internal bleeding, which can also cost lives.
Unlisted Boehringer also said there have been fewer cases of fatal side effects linked to Pradaxa than what would have been expected if they had been treated by the standard drug warfarin, which Boehringer is trying to replace.
Warfarin has been used for decades but it is difficult to handle because it interacts with certain vegetables and requires frequent blood tests.
Pradaxa, the first in a promising new class of medicines to overcome these drawbacks, is designed to prevent strokes in patients suffering from atrial fibrillation, a form of irregular heartbeat common among the elderly.
Boehringer said in its statement that the risk of deadly bleeding linked to warfarin was more than 40 percent higher than that associated with Pradaxa, citing figures from the RE-LY study that led to the new pill's approval.
Still, some healthcare watchdogs' attention has been heightened.
European regulators last month said that patients about to take Pradaxa should have their kidneys checked, and Japanese regulators told Boehringer in August to issue a strong warning to doctors of potentially deadly bleeding as a result of use of Pradaxa.
Rival anti-clotting drugs include Xarelto from Bayer and Johnson & Johnson, Eliquis from Bristol-Myers Squibb and Pfizer, and Daiichi Sankyo's Lixiana.
The are all vying for a market that analysts estimate at somewhere between $10 billion and $20 billion per year.
Pradaxa won regulatory clearance in the United States for stroke prevention in October 2010, followed by other important markets this year.
Bayer and Johnson & Johnson's Xarelto could make major gains this weekend at the annual American Heart Association meeting in Orlando, where more clinical data is due to be release
Healthy You
Middle-aged and older women with sleep problems are at greater risk
Researchers from Norway have uncovered an association between sleep problems and increased risk of fibromyalgia in women. The risk of fibromyalgia increased with severity of sleep problems, and the association was stronger among middle-aged and older women than among younger women. Results of the prospective study, based on ten years of data, appear in Arthritis & Rheumatism, a journal published by Wiley-Blackwell on behalf of the American College of Rheumatology (ACR).
Drs. Paul Mork and Tom Nilsen from the Norwegian University of Science and Technology (NTNU) investigated the impact of sleep problems on risk of fibromyalgia in a population of women in Norway. Female participants aged 20 and older who had participated in a large population-based health study (the HUNT study; http://www.ntnu.edu/hunt) by answering a health-related questionnaire and undergoing clinical examination were included in the investigation. The researchers selected 12,350 women who were free of musculoskeletal pain and movement disorders for the current study.
Exercise has long been recommended to fibromyalgia patients, and some find it improves their sense of well-being. "This is a first look at understanding how exercise alters memory performance," Walitt said of the study.
The finding potentially suggests that exercise may lead to improvement in the network of brain areas that are recruited for working memory to function.
While more study is needed, Walitt said that "overall, exercise seems to be a beneficial thing for fibromyalgia patients, in terms of overall well-being. If you can exercise and make it work for you, that's great."
While the study has some flaws, it's basically encouraging for those with the condition, said Dr. I. Jon Russell, a San Antonio fibromyalgia researcher and consultant, and retired professor at the University of Texas Health Science Center, San Antonio.
"We have many reasons to believe that aerobic exercise is good for our patients. This study gives some support [to that idea]," Russell said. However, "We shouldn't over-interpret that exercise is the answer."
Research presented at meetings should be considered preliminary since it has not undergone the scrutiny required of studies published in peer-reviewed journals.
More information
For more on fibromyalgia, visit the American Chronic Pain Association.
In Case You Missed It
On Nov. 7, 1991, Los Angeles Lakers point guard Earvin "Magic" Johnson shocked the world when he announced that he had contracted HIV, the virus that causes AIDS. After the press conference, the perception was that Johnson had just pronounced his own death sentence.
Yet, 20 years later, the now-52-year-old Johnson is going as strong as ever in his roles as a sports analyst, businessman and HIV activist. In 1991, when most of what people knew about HIV/AIDS was that it lead to death at a young age, this outcome might have seemed impossible.
So why is Johnson still alive?
"There is nothing unique about Magic," said Spencer Lieb, senior epidemiologist and HIV/AIDS research coordinator for the Florida Consortium for HIV/AIDS Research. "There are still people alive and kicking and doing very well 20 and 30 years after infection." [Does Circumcision Prevent HIV?]
Lieb said that in the state of Florida alone, hundreds of patients have hung on since becoming infected with HIV in the early 1980s, when the first confirmed AIDS cases turned up in the United States. But Johnson and these people are still in the minority: According to research and estimates by Centers for Disease Control and Prevention, about 1.2 million Americans have HIV, and only 20 percent of them are aware of it. Approximately 50,000 people become infected each year, and more than 18,000 die annually.
Stopping HIV in the back court
The key with Johnson and others has been preventing their incurable disease from progressing into full-blown AIDS.
Upon infection with human immunodeficiency virus (HIV), a person's immune system kills off nearly all of the virus and infected cells. But some small number remain, and over time, those HIV cells replicate, and replicate, and replicate. Then, usually 10 years after the initial infection, the viral load reaches a critical count, and the virus begins killing off the vital immune cells that protect us against infections.
At that critical count, a person is considered to have acquired immunodeficiency syndrome (AIDS); with the body’s immunological defenses destroyed, it's usually only a matter of months before a range of opportunistic infections and cancers complete their lethal work.
Researchers have developed a number of powerful drugs to help people like Johnson avoid this fate. The key weapon has been a regimen of three or four antiretroviral drugs, collectively known as highly active antiretroviral therapy, or HAART.
According to a Newsweek story from last spring, one of Johnson's doctors who helped pioneer the treatment placed him on the then-experimental drug cocktail in 1994, about a year and a half before it came into widespread use in 1996. [Top 10 Stigmatized Health Disorders]
"Magic got a jumpstart on experimental drugs before they were released to the general public," Lieb told Life's Little Mysteries, "but there were many people in clinical trials benefitting at the same time."
The meds that slam dunk HIV
HIV spreads by hijacking a subset of white blood cells called T cells, which are the body's first line of defense against foreign invaders, and using the cells' DNA to make copies of itself or replicate; in this process, these T cells get destroyed. The most common drugs in the HAART regimen target two of the enzymes that HIV uses to replicate itself.
The first enzyme, called reverse transcriptase, turns the virus' genetic instructions encoded in a single RNA strand into double-stranded DNA. (In scientific terms, this mode of replication classifies HIV as a retrovirus, hence "antiretroviral" drugs.)
The second enzyme, known as protease, creates new, functional HIV virus particles by cutting up the proteins cranked out by our hijacked cellular machinery.
Medication can disrupt these processes, and to that end, Johnson is currently taking reverse transcriptase inhibitor and protease inhibitor drugs, which are contained in the pharmaceuticals Trizivir and Kaletra, respectively, as reported by Newsweek.
Although these and other HIV-fighting drugs are "hideously expensive," Lieb noted, so are a substantial number of prescription drugs for much more everyday diseases.
Public and private medical insurance, as well as various assistance programs, make the medicines affordable and available to the vast majority of patients in the United States and other parts of the world. It is a "myth," said Lieb, that Johnson, who is wealthy, is buying himself special treatments.
Staying in the game
By taking the right regimen every day, most HIV patients can see the number of virus particles in a sample of their blood, or viral load, become undetectably low.
Not only does a low viral count stave off symptoms of HIV and AIDS, but it also slashes the odds of a randomly mutated copy of the virus emerging that can prove resistant to the therapy. Furthermore, a low viral load severely reduces the risk of transmitting the virus to others.
Yet even without modern drugs, in rare instances an HIV-positive person can manage on their own to keep AIDS at bay. These "long-term nonprogressors" or "elite controllers," estimated at as few as one in 500, have lived for decades with HIV, despite not being on antiretroviral therapy.
It is not known if Johnson is among this "scarce breed," as Lieb called them, but more than likely "without medications, he'd be progressing."
Researchers continue to study long-term nonprogressors for get insights on HIV resistance that could help the 33 million people battling the virus.
As Johnson has prominently shown, however, those with HIV can still live productive lives. Lieb has seen many such promising cases in person. "We have very buff-looking, healthy-looking HIV patients who have been infected for ages," Lieb said. "You can't tell the difference between them and you and me."
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