“Systems,” by Dan Beckemeyer
HCV Abstract Corner
Monthly Pubmed Review of the most relevant research on hepatitis C.
Jan 2012
Open publication - Free publishing
Tylenol And The Liver
Featured Fact Sheet From HCV Advocate:
Acetaminophen and You Liver
Learn about how the liver processes Tylenol (acetaminophen) and what the dangers are of accidental overdose.
Click Here
Acetaminophen and You Liver
Learn about how the liver processes Tylenol (acetaminophen) and what the dangers are of accidental overdose.
Click Here
Anemia During HCV Therapy
January 24, 2012
In opposition to what seems logical, research demonstrates that becoming anemic while on Hepatitis C therapy is not such a bad thing.
The Outcomes and Management of Anemia in the Phase III Trials of Boceprevir and Telaprevir
Source CCO
Source CCO
Brian L. Pearlman, MD, FACP
Posting Date: December 13, 2011
Medical Director, Center for Hepatitis C
Atlanta Medical Center
Atlanta, Georgia
Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Associate Professor of Medicine
Emory School of Medicine
Atlanta, Georgia
Atlanta Medical Center
Atlanta, Georgia
Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Associate Professor of Medicine
Emory School of Medicine
Atlanta, Georgia
Dec 2011
Editor’s note: In this edition of Journal Options Hepatitis, we feature the 5 pivotal phase III studies that led to the approval in 2011 of boceprevir and telaprevir for the treatment of chronic hepatitis C. Each commentary in this series addresses a key issue or question of clinical relevance related to the use of these agents in clinical practice.
In the pivotal phase III studies of the protease inhibitors boceprevir or telaprevir, which led to their approval for treatment of genotype 1 hepatitis C virus (HCV), anemia was an important adverse event observed in both treatment-naive and treatment-experienced patients for both medications.[1-4] In the telaprevir ADVANCE trial of treatment-naive patients, an additional 18% to 20% of the study population experienced anemia on a telaprevir-containing regimen compared with the control arm of peginterferon/ribavirin (37% to 39% vs 19%, respectively).[1] The same comparison in the SPRINT-2 trial showed that anemia occurred in an additional 20% of treatment-naive patients receiving a boceprevir-containing regimen compared with control (49% vs 29%, respectively).[2] Likewise, in the treatment-experienced trials, anemia rates with either protease inhibitor exceeded those observed in the peginterferon/ribavirin control arm by at least 15%. In the REALIZE trial, anemia rates were 30% to 36% in the telaprevir-containing arms vs 15% in the control arm,[3] and RESPOND-2 reported anemia among 45% in the boceprevir-containing arms vs 20% in the control arm.[4] Of note, the seemingly higher rates of anemia in boceprevir vs telaprevir trials are possibly due to the extended exposure of the drug rather than a true greater impact of the drug on anemia development.
In the registration trials for boceprevir, anemia was managed with ribavirin dose reduction and/or with off-label use of erythropoietin.[2,4] In clinical trials, 43% of anemic patients received erythropoietin (vs 24% in the control arms). Similar to the association between the development of anemia and improved sustained virologic response (SVR) rates with peginterferon/ribavirin observed in the era prior to the introduction of direct-acting antivirals,[5] patients who became anemic on triple therapy in the SPRINT-2 trial attained superior SVR rates compared with those who did not become anemic.[2] Among patients who did not develop anemia, the SVR rate was 58%, whereas SVR rates ranged from 71% to 78% in those who did become anemic. SVR rates were similar whether the investigator chose to manage anemia with ribavirin dose reduction (78% [29/37]), erythropoietin (74% [95/129]), or both (71% [109/153]), as shown in Figure 1.[6] A similar pattern was seen in the RESPOND-2 trial. Apparently, patients who become anemic during peginterferon/ribavirin therapy have higher ribavirin plasma concentrations. Even when ribavirin doses are reduced, plasma levels are sufficient to maintain the medication’s efficacy.[7]
Figure 1. SVR rates according to management strategy in patients receiving boceprevir.[6]
In contrast with the boceprevir trials, only ribavirin dose reduction was used in the telaprevir trials to manage anemia, as growth factors were strictly prohibited in the protocols.[1,3] Also in contrast with boceprevir, no overall relationship was identified between anemia development and SVR rates in a pooled analysis of treatment-naive patients from ADVANCE and ILLUMINATE who were treated with telaprevir for 12 weeks.[8] SVR rates were 74% for patients with a hemoglobin level that fell to < 10 g/dL and 73% for patients whose hemoglobin remained at ≥ 10 g/dL.[8] However, in the control arms without the protease inhibitor, anemia development corresponded with an improved SVR rate compared with patients who did not become anemic (50% vs 41%, respectively). Of note, however, when analyzed according to degree of hemoglobin change from baseline, patients with a < 3 g/dL reduction in hemoglobin achieved an SVR rate of 55% (61/111), whereas the SVR rate was 76% (590/774) among individuals who experienced a reduction of ≥ 3 g/dL from baseline. Finally, this pooled analysis showed that ribavirin dose reduction had no apparent effect on SVR in the telaprevir-containing arms (12 weeks) but seemed to have a deleterious effect on SVR in the arms without the protease inhibitor (Figure 2).
Figure 2. ADVANCE/ILLUMINATE: impact of ribavirin dose reduction on SVR.[8]
The prescribing information for both boceprevir and telaprevir advise that anemia should be managed through ribavirin dose reductions. Although it would appear that ribavirin dose reduction is a reasonable management strategy for patients who develop anemia while receiving boceprevir- or telaprevir-containing triple therapy, the reader should note that the aforementioned data were garnered from retrospective analyses. An ongoing manufacturer-sponsored prospective trial may further clarify the decision to either dose reduce ribavirin or to use off-label erythropoietin when a prescriber is confronted with therapy-induced anemia.[9] Of note, protease inhibitors cannot be dose reduced and must be discontinued if ribavirin (or peginterferon) is discontinued for any reason.
Anemia can develop rapidly and may be severe. In my practice, and in discussions with other high-volume treaters, we are finding that anemia can occur very rapidly—within 2 weeks of protease inhibitor introduction. The rapid development seen in clinical practice is likely due to the different patient characteristics of individuals within a practice when compared with those eligible for inclusion within clinical trials. Because of this potential for rapid and severe anemia development, I have selected a more aggressive monitoring strategy in my practice and begin evaluation of hemoglobin levels within 2 weeks of treatment initiation and continue to monitor levels every 4 weeks.
Please review the remaining 4 commentaries in this series on the use of boceprevir and telaprevir in clinical practice:
Free registration is required to view the below links
- To review strategies for management of telaprevir-associated rash and anorectal symptoms, click here.
- For a better understanding of futility rules and their importance with boceprevir and telaprevir, click here.
- To review the impact of the occurrence and management of anemia with boceprevir and telaprevir, click here.
- To review rules for following response-guided therapy guidelines with telaprevir and boceprevir, click here.
Cirrhosis-Varices
Less Terlipressin Effective in Variceal Bleeding
By David Douglas
NEW YORK (Reuters Health) Jan 30 - The usual three days of terlipressin treatment after ligation of bleeding esophageal varices could possibly be cut down to a single day, according to Pakistani researchers.
Overall, a 24-hour course of terlipressin was not inferior to 72 hours of treatment after endoscopic variceal band ligation (EVBL).
On the basis of this trial and a previous one, the researchers say they "may recommend shortening the duration of therapy in future guidelines."
However, Dr. Saeed S. Hamid added in an email to Reuters Health, until "others have had a chance to comment on it," he and his colleagues are not yet ready to suggest that the shorter course be the standard of care.
In a report online December 16th in the Journal of Hepatology, Dr. Hamid and colleagues note three to five days of vasoactive drugs are usually advised in addition to EVBL when varices bleed. However, the optimal duration in any given patient has not been established. Moreover, the team has found that particularly when the risk of rebleeding is low, 24 hours appears effective.
To investigate further, the researchers randomized 130 patients to receive terlipressin for 24 or 72 hours. Most patients were men and had hepatitis C virus infection. All had open-label terlipressin for the first 24 hours and then switched to active or dummy treatment.
Bleeding was controlled in everyone in the short-course group but there was one failure in the standard course group within 5 days. At 30 days, there was no difference in rebleeding rates, although the number in the control group was numerically lower: 3.1% and 1.5%.
At 30 days, there were 12 deaths from any cause (six in each group), and seven patients in each group reached the composite outcome of re-bleeding and/or death.
Overall, the short course was not inferior to longer term use.
If indeed the treatment could be safely shortened, Dr. Hamid said, there would be "significant cost implications, as well as perhaps implications on the safety of the drug without losing efficacy."
SOURCE: http://bit.ly/yYxQrf
J Hepatol 2011.
Source-Medscape
Discussion Only
Click Here For Full Text
In this study, we explored the potential influence of various baseline and on-treatment factors, including serum ribavirin concentrations, on nonresponse to PEG-interferon alfa-2b and ribavirin in treatment-naive CHC patients. Our main finding is that lower week-24 serum ribavirin concentrations are an independent risk factor for nonresponse.
This finding indicates the importance of adequate exposure to ribavirin, especially in HCV genotype 1–4 patients. Only 3% of patients with HCV genotype 2–3 were nonresponders, but all had a serum ribavirin concentration below 2 mg/L. Although one could speculate that a certain threshold in serum ribavirin concentrations has to been reached to exclude an unfavourable outcome in patients with HCV genotype 2–3, the low numbers of genotype 2–3 patients with nonresponse preclude any conclusion in this respect.
Inter-patient variability in serum ribavirin concentrations is known to be high.[5,6] Body weight, renal function, gender and age are associated with ribavirin clearance at various time points but can only explain a small part of the variability.[5,15,16] In our study, only higher average ribavirin doses (in mg/kg per day) were an independent predictor of higher serum ribavirin concentrations (r 2 = 0.029). Determinants not studied in the current analysis such as nonadherence[17] and factors influencing absorption, transport and intracellular metabolism of ribavirin could contribute to the high variability.
Ribavirin has a narrow therapeutic index: while low ribavirin concentrations increase the risk of nonresponse, high ribavirin concentrations increase the risk of toxicity, especially haemolytic anaemia.[5,7,8,18,19] In line with these data, week-24 haemoglobin decreases in the current study were significantly correlated with week-24 ribavirin concentrations (r = 0.42, P < 0.001).
A potential bias in our analysis is that only patients who completed 24 weeks of treatment were included. However, only two patients stopped therapy before week 24 because of anaemia. We were interested in week-24 serum ribavirin concentrations, because we aimed at identifying factors determining risk of nonresponse rather than to adapt ribavirin dose at an early point during antiviral therapy. However, according to previous literature, steady state concentrations are already reached after 4–8 weeks.[20] Another possible limitation of this study is that we did not measure serum PEG-interferon concentrations. It should also be noted that some aspects of the study protocol differ from current practice, because the design of the CIRA study dated from 1999–2000.[12] Patients received high-dose induction therapy with interferon, which is currently not advised. PEG-interferon alfa-2b dose was decreased in the second half of the treatment period from 1.5 to 1.0 μg/kg per week.
However, PEG-interferon doses 1.0 μg/kg per week appear not to compromise SVR rates.[21,22] Also, in our series of 236 patients with ribavirin determinations, there was one outlier, with ribavirin concentration of 7.4 mg/L. Although we cannot exclude some haemolysis associated with antiviral therapy in this patient, all available clinical data would suggest that ribavirin exposure was considerable: the patient received a high ribavirin dose (17.5 mg/kg per day), with corresponding drop in haemoglobin (3.6 mm at week 24 compared to basal). Finally, patients were not checked after 12 weeks of treatment for early viral response,[23] and patients with HCV genotype 2–3 were treated for 1 year.
Apart from lower serum ribavirin concentrations, infection with HCV genotype 1–4 and higher baseline γ-GT levels were identified as independent risk factors for nonresponse. HCV genotype 1 has extensively been described as the predominant risk factor for nonresponse to combination therapy for CHC. In our study, HCV genotype 1–4 was the predominant predictor for nonresponse. In contrast, elevated γ-GT levels have not been described as an independent predictive factor for nonresponse in patients with hepatitis C before. However, low or normal γ-GT levels have been associated with SVR,[24–26] and our findings suggest that lower nonresponse rates under these circumstances could be the explanation of this finding. Elevated γ-GT levels are associated with more severe hepatic fibrosis or cirrhosis.[27,28] In the current analysis, 54% of patients exhibited elevated γ-GT levels, similar to other reports,[25,26,29,30] and γ-GT levels were significantly correlated with severe fibrosis or cirrhosis (median of γ-GT level 70 (range 16–700) in case of severe fibrosis or cirrhosis vs 48 (5–575) in case of less severe fibrosis scores, P = 0.004). Severe fibrosis or cirrhosis could not be identified as a predictive factor for nonresponse, and one may speculate that γ-GT is a more sensitive marker for fibrosis than classification according to the METAVIR scoring system.
We also compared various on-treatment factors suggested to be different on re-treatment between patients with partial response and null response in the HALT-C trial[11] to evaluate whether similar differences could be found in treatment-naive patients. The predictive value of less reduction in body weight, leucocytes and platelets for nonresponse was not confirmed in our treatment-naive patients. Nevertheless, when comparing partial responders with null responders, a trend towards less reduction in body weight, leucocytes, granulocytes and platelets was observed, suggesting type II error. Alternatively, interferon-related factors may predict null response, especially during re-treatment of previous nonresponder patients and/or patients with severe fibrosis/cirrhosis. No other relevant studies on this topic have been published.
In conclusion, our results indicate that ribavirin rather than PEG-interferon pharmacodynamics determine in part the chance of nonresponse in treatment-naive CHC patients. This is especially the case in patients with HCV genotype 1–4, although HCV genotype 2–3 patients with serum ribavirin concentrations below a threshold of 2.0 mg/L may also experience nonresponse.
Generic Drugs ?
Source Pharmalot
A group of physicians - mostly, family medicine docs and internists - were asked about their views on prescribing lower-cost copycat meds, in general.
65 percent reported that they have experienced a failure with a generic equivalent where the brand-name drug was successful. And 94 percent reported that their own patients had indicated a generic did not work as well as the branded drug they were taking previously, according to DoctorDirectory, a firm that specializes in brand-name marketing....continue reading
Just Because
Newswise — Say “I love you” with flowers, chocolates or a greeting card, but be careful when you kiss this Valentine’s Day.
“Mid-February is usually the peak season for infectious diseases, such as the seasonal and H1N1 flu, mononucleosis, colds and coughs,” says Jorge Parada, MD, medical director, infectious disease at Loyola University Health System. “And don’t rely on obvious signs of illness - such as sneezing or fever as a tip off. People with infectious diseases start shedding the virus before they experience the full effect of the illness.”
Changing weather or temperatures are often blamed for winter’s coughs and sniffles. But in reality, colds, coughs and the flu are infectious diseases “caught” through transmission from one human to another.
“Becoming too hot or too cold can cause stress to the body, weaken the defense in fighting off infections and thus make us more vulnerable,” said Parada, who is also a professor of preventive medicine at Stritch School of Medicine. “But a person has to be exposed to a virus or bacteria to catch it.” Dr. Parada feels that winter trends such as staying indoors in crowded arenas such as shopping malls or movie theatres may promote winter colds and flu.
Drink to Me Only with Thine Eyes
Drinking from the same wine glass or sharing dessert with the same fork may seem romantic, but also may lead to infections.
Drinking from the same wine glass or sharing dessert with the same fork may seem romantic, but also may lead to infections.
And keep your chopstick to yourself.
“Someone can have a cold sore that hasn’t erupted yet and use lip balm which is then shared, and the cold sore virus – otherwise known as herpes - is transmitted,” said Parada. Albeit less frequently, shared linens also are transmitters of infections. “A shared pillowcase, napkin or towel can also actually be a conduit for disease, especially if someone has a sore or cut,” says Parada.
Do’s and Don’ts For Safe Displays of Affection
Do Give and Get a Flu Shot – “It’s the gift that keeps on giving – you protect yourself, your loved one and you stop the virus from spreading to others,” said Parada. “If that isn’t sexy, and say ‘I love you’ I don’t know what does.”
Don’t Share Utensils – “Humans can transmitsome infections through saliva. A glass, fork or napkin can act as a bridge and pass the bug along to another person when that shared object is used by one infected person and then used by another.”
Don’t Kiss or Have Close Body Contact if You Feel Unwell – “Throwing up and blowing your nose is not fun; no one wants to be ill so being upfront and honest when you feel under the weather will be appreciated.”
Don’t Kiss or Have Close Body Contact if You Feel Unwell – “Throwing up and blowing your nose is not fun; no one wants to be ill so being upfront and honest when you feel under the weather will be appreciated.”
Give The Flu The Kiss-Off
Parada says that it takes 10 – 14 days after injection for the flu shot to have full preventive effect. “Get that flu shot now to increase your odds for romance on Valentine’s Day,” says Parada. “Having a flu shot is definitely sexy. It beats the flu every time!”
Parada says that it takes 10 – 14 days after injection for the flu shot to have full preventive effect. “Get that flu shot now to increase your odds for romance on Valentine’s Day,” says Parada. “Having a flu shot is definitely sexy. It beats the flu every time!”
Off The Cuff
Source Medgadget
A year ago we reported on a nifty use of augmented reality technology to display tomography images virtually right on the body of the patient who was scanned.
The project, called “mirracle,” is spearheaded by researchers from Technical University of Munich who have been improving the interactivity of the system over the last year to make it more intuitive and easy to use. Here’s the latest demo video of the latest iteration of the magic mirror:
Read More
IOM publishes call to action on chronic disease
Source Spoonful Of Medicine-Nature
A report published today by the US Institute of Medicine (IOM) calls for an overhaul of the way public health departments conduct surveillance and treatment of chronic diseases ranging from arthritis to depression. The report, co-sponsored by the US Centers for Disease Control and Prevention (CDC) and the Arthritis Foundation, both based in Atlanta, warns that chronic disease, which accounts for three quarters of healthcare spending in the United States, is an overlooked crisis. The authors argue that the CDC can use funds more efficiently by expanding surveillance systems, integrating community health systems in schools and workplaces and prioritizing patient education.
The report, Living Well with Chronic Illness, focuses on nine chronic conditions. In addition to cancer and type 2 diabetes, diseases for which substantial public health initiatives already exist, it names mental illnesses such as dementia, post-traumatic stress disorder, schizophrenia and depression.
Such diseases decrease the productivity and quality of life of millions of Americans, but public health departments do not adequately address such illnesses, the report argues, in part because surveillance systems fail to assess the needs of patients with chronic disease. For example, little information exists about how people with chronic illnesses such as arthritis access healthcare and what interventions are most effective at increasing their productivity and decreasing the cost of managing the disease.
“Historically, when infectious diseases were the dominant thing, that was what surveillance systems counted,” says Robert Wallace, a physician at the University of Iowa and the chairman of the committee that produced the report. “But now there are enormous numbers of people with chronic illnesses and not enough information about what is and is not working in the public health sphere.”
At the core of the report’s recommendations is a call for the CDC to enact policies that empower people to seek care for chronic diseases. Such policies could include integrating health services in schools and workplaces to encourage healthy lifestyle choices that can prevent or mitigate chronic illness. The report also stresses the importance of getting individuals into the healthcare system early and helping them navigate care options to avoid confusion and alienation.
John Klippel, president of the Arthritis Foundation, says the IOM’s decision to issue a report on chronic illness is timely, and he hopes the public pays attention. “I don’t know that the public quite recognizes the importance and magnitude of chronic illness,” he says. “The effects of these illnesses on lifestyle and quality of life are profound. We need to use resources better, but we also need to empower people to take control of their own care.”
The project, called “mirracle,” is spearheaded by researchers from Technical University of Munich who have been improving the interactivity of the system over the last year to make it more intuitive and easy to use. Here’s the latest demo video of the latest iteration of the magic mirror:
Read More
Uploaded by HCPLiveTV on Jan 12, 2012
Paul Kwo, MD, FACG, professor of medicine in the division of gastroenterology and hepatology at the Indiana University School of Medicine, discusses a program in which hepatitis C screening was offered to patients aged 50 to 65 during routine colonoscopy. He explains that these patients are prime candidates for undiagnosed hepatitis C infection due to high-risk behavior they may have engaged in several decades ago and that screening during colonoscopy offers gastroenterologists an opportunity to reduce morbidity and mortality due to hepatitis C. This video was shot during the annual scientific meeting of the American College of Gastroenterology in Washington, DC.
IOM publishes call to action on chronic disease
Source Spoonful Of Medicine-Nature
A report published today by the US Institute of Medicine (IOM) calls for an overhaul of the way public health departments conduct surveillance and treatment of chronic diseases ranging from arthritis to depression. The report, co-sponsored by the US Centers for Disease Control and Prevention (CDC) and the Arthritis Foundation, both based in Atlanta, warns that chronic disease, which accounts for three quarters of healthcare spending in the United States, is an overlooked crisis. The authors argue that the CDC can use funds more efficiently by expanding surveillance systems, integrating community health systems in schools and workplaces and prioritizing patient education.
The report, Living Well with Chronic Illness, focuses on nine chronic conditions. In addition to cancer and type 2 diabetes, diseases for which substantial public health initiatives already exist, it names mental illnesses such as dementia, post-traumatic stress disorder, schizophrenia and depression.
Such diseases decrease the productivity and quality of life of millions of Americans, but public health departments do not adequately address such illnesses, the report argues, in part because surveillance systems fail to assess the needs of patients with chronic disease. For example, little information exists about how people with chronic illnesses such as arthritis access healthcare and what interventions are most effective at increasing their productivity and decreasing the cost of managing the disease.
“Historically, when infectious diseases were the dominant thing, that was what surveillance systems counted,” says Robert Wallace, a physician at the University of Iowa and the chairman of the committee that produced the report. “But now there are enormous numbers of people with chronic illnesses and not enough information about what is and is not working in the public health sphere.”
At the core of the report’s recommendations is a call for the CDC to enact policies that empower people to seek care for chronic diseases. Such policies could include integrating health services in schools and workplaces to encourage healthy lifestyle choices that can prevent or mitigate chronic illness. The report also stresses the importance of getting individuals into the healthcare system early and helping them navigate care options to avoid confusion and alienation.
John Klippel, president of the Arthritis Foundation, says the IOM’s decision to issue a report on chronic illness is timely, and he hopes the public pays attention. “I don’t know that the public quite recognizes the importance and magnitude of chronic illness,” he says. “The effects of these illnesses on lifestyle and quality of life are profound. We need to use resources better, but we also need to empower people to take control of their own care.”
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