Management of anemia induced by triple therapy in patients with chronic hepatitis C

Management of anemia induced by triple therapy in patients with chronic hepatitis C: challenges, opportunities and recommendations

Manuel Romero-Gómez , Marina Berenguer, Esther Molina , José Luis Calleja

Received 6 May 2013; received in revised form 20 June 2013; accepted 8 July 2013. published online 17 July 2013.

Accepted Manuscript
To read the body of this article, please view the PDF online

Abstract
The addition of protease inhibitors, boceprevir or telaprevir, to peginterferon + ribavirin increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy.

Most significant factors associated with anemia in patients receiving triple therapy include older age, lower body mass index (BMI), advanced fibrosis and lower baseline hemoglobin. The variability in inosine triphosphate pyrophosphatase (ITPA) gene, which encodes a protein that hydrolyses inosine triphosphate (ITP), has been identified as an essential genetic factor for anemia both in dual and triple therapy. The correct management of anemia is based on anticipation, characterization and therapeutic management. Basically, anemia can be characterized in 3 types: ferropenic (mostly in fertile women), thalasemic type hemolytic anemia and anemia from chronic processes. Functional deficit of iron should also be excluded in patients with normal ferritin and lower saturation of transferrin. Ribavirin dose reduction and Epoetin, sequentially, are indicated in the management of anemia. Epoetin non-response can be caused by lack of time, type of anemia, functional iron deficit or erythropoietin resistance.

In the transplantation setting, adding a protease inhibitor to peginterferon + ribavirin results in a significant increase in the incidence and severity of anemia and, as a consequence, a greater need for Epoetin, transfusions and ribavirin dose reductions. Packed red cell transfusions are utilized when hemoglobin decreases to less than 7.5 g/dL and/or there are clinical symptoms and/or there is no response to other therapeutic measures.

HCV treatment improves survival among anemic patients

HCV treatment improves survival among anemic patients

Mohanty A. Clin Gastroenterol Hepatol. 2013;11:741-747.

June 6, 2013
While anemia increased mortality rates among patients with hepatitis C, those who underwent treatment for the infection experienced significantly improved survival in a recent study.

Researchers performed a retrospective analysis of 200,139 veterans with chronic hepatitis C, including 29,510 with anemia, as well as 195,166 controls without HCV. Patients had been enrolled in the Electronically Retrieved Cohort of Hepatitis C-Infected Veterans between 2001 and 2008. HCV treatment was initiated in 1,820 patients with and 17,755 without anemia.

Anemia was more prevalent among patients with HCV than controls (14.7% vs. 12.5%; P<.001). Multivariate analysis indicated significant associations between pretreatment anemia and decompensated liver disease (OR=3.69; 95% CI, 3.53-3.86), chronic kidney disease (OR=3.36; 95% CI, 3.23-3.51) and black race (OR=2.03; 95% CI, 1.95-2.11).

Patients with anemia were significantly less likely to initiate HCV therapy (OR=0.56; 95% CI, 0.56-0.62), with the likelihood of treatment decreasing proportionally with anemia severity (P<.001 for trend).While mortality rates were higher among anemic patients (139.2 per 1,000 person-years vs. 35.9 per 1,000 person-years among those without anemia), treated anemic participants had lower all-cause mortality rates than untreated anemic patients (54.2 per 1,000 person-years vs. 146.8 per 1,000 person-years).

Investigators calculated an adjusted HR of 0.45 (95% CI, 0.39-0.51) for HCV treatment among anemic participants after adjustment for covariates. This risk reduction was similar to that observed among participants without anemia (aHR=0.44; 95% CI, 0.41-0.48), and was not impacted by anemia severity. Sensitivity analysis excluding those with major comorbidities (n=5,925, HCV patients with anemia; n=69,478, without anemia) yielded similar results, including a greater risk reduction among treated participants (HR=0.28; 95% CI, 0.22-0.37).

“Our study shows the importance of identifying and treating individuals with chronic HCV infection who have pretreatment anemia,” the researchers concluded. “Treatment for HCV infection in anemic individuals confers a significant survival advantage after adjusting for numerous comorbidities. A better understanding of pathways that lead to baseline anemia in chronic HCV-infected individuals and targeted therapies to treat this may allow HCV treatment for a higher proportion of individuals.”

Disclosure: The researchers report numerous financial disclosures.

http://www.healio.com/infectious-disease/hepatitis-resource-center-2013/hcv-treatment-improves-survival-among-anemic-patients

Incident anemia improved response to peginterferon, ribavirin, boceprevir in HCV patients

Incident anemia improved response to peginterferon, ribavirin, boceprevir in HCV patients

Sulkowski MS. Hepatology. 2013;doi:10.1002/hep.26096.

February 15, 2013

Patients with chronic hepatitis C who developed anemia during treatment with pegylated interferon alfa-2b, ribavirin and boceprevir were more likely to experience sustained virologic response in a recent study.

As part of the Serine Protease Inhibitor Therapy 2 (SPRINT-2) Trial, 1,097 patients with chronic HCV genotype 1 randomly were assigned either peginterferon and ribavirin (PegIFN/RBV) with placebo or 800 mg boceprevir (BOC) three times a day for 44 weeks or response-guided PegIFN/RBV with BOC, following 4 weeks of lead-in therapy with PegIFN/RBV. Nearly all patients (n=1,080) had hemoglobin (Hb) levels measured during the study. Anemia (Hb below 10 g/dL) was managed with erythropoietin and/or RBV dose reduction.

Half of BOC recipients developed anemia during the study, compared with 31% of placebo recipients (P<.001). Severe anemia (Hb below 8.5 g/dL) occurred in 4% of placebo recipients and 7% BOC patients (P=.04). Patients who developed anemia had significantly lower Hb levels at baseline and estimated creatinine clearance and were more likely to use statins. Multivariate analysis indicated that baseline Hb was predictive of incident anemia (OR=0.58, 95% CI, 0.51-0.67) while low creatinine levels approached statistical significance (P=.0524).

Rates of SVR (72% vs. 58%) and response at end-of-treatment (81% vs. 67%) were higher among anemic patients than in nonanemic patients. SVR rates did not vary significantly based on anemia management method (range 70%-74%). Investigators noted that SVR rates were higher among anemic patients who experienced a maximum decline of more than 3 g/dL during treatment.

“The addition of BOC to PegIFN/RBV therapy is associated with greater risk of anemia compared with PegIFN/RBV alone,” the researchers wrote. “However, the SVR rate was higher in patients with incident anemia compared with those without anemia irrespective of the anemia management strategy. Additional studies are under way to further evaluate these strategies to management treatment-emergent anemia. Until such data is available, RBV dose reduction should remain the primary approach to anemia management during BOC [with PegIFN/RBV] therapy for treatment-naive patients.”

Disclosure: See the study for a full list of relevant disclosures.

http://www.healio.com/hepatology/chronic-hepatitis/news/online/%7B81B91D64-4D47-411F-BB99-0C6D8C28D570%7D/Incident-anemia-improved-response-to-peginterferon-ribavirin-boceprevir-in-HCV-patients
 

Ribavirin dose reduction, erythropoietin combat HCV anemia

By: NEIL OSTERWEIL, Family Practice News Digital Network

BOSTON – Anemia developed significantly more often among patients with hepatitis C virus infection and compensated cirrhosis than among noncirrhotic patients during triple therapy in a randomized, open-label trial of treatment-naive patients, but in most instances the anemia was effectively treated.

In an anemia management subanalysis of a study comparing sustained virologic response (SVR) rates in cirrhotic and noncirrhotic patients treated with boceprevir (Victrelis), pegylated interferon alfa-2b (Peg-Intron), and ribavirin (RBV), 57% of patients with cirrhosis and anemia treated with a ribavirin dose reduction had an SVR, compared with 64% of those treated with erythropoietin. Among noncirrhotic patients with anemia, the respective SVR rates were 73% and 72%; none of the differences was significant, Dr. Eric J. Lawitz reported at the annual meeting of the American Association for the Study of Liver Diseases.

Courtesy US. Dept of Veterans Affairs "Sustained viral responses are comparable in cirrhotic patients when anemia is managed by ribavirin dose reduction or erythropoietin," said Dr. Eric J. Lawitz.

"Sustained viral responses are comparable in cirrhotic patients when anemia is managed by ribavirin dose reduction or erythropoietin," said Dr. Lawitz, medical director and principal investigator at Alamo Medical Research in San Antonio, Tex., adding that ribavirin dose reductions should be the initial strategy for managing anemia, followed, if necessary, by erythropoietin.

In the trial, 687 treatment-naive patients with hepatitis C virus (HCV) infections were treated for 4 weeks with pegylated interferon (PEG-IFN) alfa-2b and RBV, then 24 or 44 weeks of boceprevir added in. Baseline hemoglobin levels ranged from 12 g/dL to15 g/dL for women, and from 13 g/dL to15 g/dL for men.

Patients with a hemoglobin level approaching 10 g/dL or less (tested from baseline through week 48) were randomized to either ribavirin dose reduction (249 patients) in 200-mg increments (first increment of 400 mg for initial 1,400-mg daily doses) at the investigators’ discretion, or to erythropoietin (251 patients) at 40,000 U/wk, modifiable to 20,000 U/wk or 60,000 U/wk at the investigator’s discretion. The remaining patients received anemia prophylaxis but were not randomized.

If the hemoglobin level dropped to 8.5 g/dL, patients could receive the other treatment as a secondary intervention, and patients with a hemoglobin level of 7.5 g/dL were discontinued from all study drugs.

Primary efficacy measures for all patients (cirrhotic and noncirrhotic) in each anemia strategy group were identical, with 82% having an end-of-treatment response, 71% having an SVR, and 10% experiencing relapse.

Among cirrhotic vs. noncirrhotic patients, rates were 68% vs. 76% for end-of-treatment response , 55% vs. 64% for SVR, and 18% vs. 11% for relapse.

Patients with cirrhosis were significantly more likely to require a secondary anemia intervention (44% vs. 26%, P = .009). Among noncirrhotic patients (but not cirrhotic patients), a secondary anemia intervention was associated with a greater likelihood of SVR (80% vs. 70% for only one intervention, P = .05).

Serious adverse events occurred in 20% of cirrhotic patients and 12% of noncirrhotic patients, but only one study death occurred. The noncirrhotic patient died of a cardiac arrest, which was considered to be unrelated to therapy.

Treatment-emergent adverse events occurred in 3% of patients with cirrhosis and 2% of those without cirrhosis. Drug discontinuation for adverse events occurred in 17% of cirrhotic patients, and 16% of noncirrhotic patients.

Cirrhotic patients were more likely to have hemoglobin concentrations ranging from 6.5 to 8.0 g/dL than were noncirrhotic patients, but no patient in either group had a hemoglobin concentration below 6.5 g/dL.

Neutrophil counts in the range of 500-749/mm³ occurred in 24% of cirrhotic patients and 27% of noncirrhotic patients, and counts below 500/mm³ were seen in 20% and 12%.

Platelet counts from 25,000 to 49,999/mm³ occurred in 22% of cirrhotic patients and 2% of noncirrhotic patients. Counts below 25,000/mm³ were seen in 3% vs. less than 1%, respectively. Transfusion rates were similar between the groups.

The study was funded by Merck Sharp & Dohme, which manufactures boceprevir. Dr. Lawitz disclosed receiving grant and research support from the company.

 

http://www.familypracticenews.com/news/infectious-diseases/single-article/ribavirin-dose-reduction-erythropoietin-combat-hcv-anemia/39518232404e3b7f0a32e5c22e47cee0.html

AASLD-Phase III Analyses on Anemia Management With Victrelis (Boceprevir) Combination Therapy, Including Cirrhotic Patients

Merck Reports New Phase III Analyses on Anemia Management Strategies Used With Victrelis (Boceprevir) Combination Therapy, Including Cirrhotic Patients

Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced results of retrospective sub-analyses from a Phase III, open-label study designed to compare the impact of two anemia management strategies – ribavirin dose reduction and an investigational use of erythropoietin (EPO) – on sustained virologic response (SVR)¹ in patients with chronic hepatitis C virus (HCV) genotype 1 infection treated with VICTRELIS^® (boceprevir) 200 mg Capsules in combination with peginterferon alfa and ribavirin (PR). These data will be presented this week at The American Association for the Study of Liver Diseases 2012 Annual Meeting (AASLD).

In the sub-analysis evaluating eligible patients who were randomized to receive ribavirin dose reduction for anemia management, SVR rates were generally similar regardless of when patients began ribavirin dose reduction, the number of steps of ribavirin dose reduction, or the lowest ribavirin dose of 400 to 1,000 mg/day received for at least 14 days for anemia management. However, SVR rates were lower in patients who received less than 50 percent of their total assigned dose of ribavirin compared to those who received at least 50 percent of their assigned dose. SVR rates were higher in those patients who had undetectable HCV RNA than those who had detectable HCV RNA at the start of their anemia management intervention, and these respective SVR rates were the same regardless of anemia management strategy.

“These analyses further confirm that ribavirin dose reduction should be the primary strategy for managing anemia in patients taking VICTRELIS combination therapy, including cirrhotic patients,” said Fred Poordad, M.D., chief medical officer, Alamo Medical Research, and professor of medicine at the University of Texas Health Science Center, San Antonio.

Indications and usage for VICTRELIS (boceprevir)
VICTRELIS is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in combination with peginterferon alfa and ribavirin (PR), in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

The following points should be considered when initiating VICTRELIS for treatment of chronic HCV infection:

• VICTRELIS must not be used as monotherapy and should only be used in combination with PR.
• VICTRELIS efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.
• VICTRELIS in combination with PR has not been studied in patients documented to be historical null responders (less than a 2 log₁₀ HCV-RNA decline by treatment week 12) during prior therapy with PR. The clinical studies included patients who were poorly interferon responsive. Patients with less than 0.5 log₁₀ HCV-RNA decline in viral load at treatment week 4 with PR alone are predicted to have a null response (less than a 2 log₁₀ viral load decline by treatment week 12) to PR therapy.
• Poorly interferon responsive patients who were treated with VICTRELIS in combination with PR have a lower likelihood of achieving a sustained virologic response (SVR), and higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to PR.

Anemia and/or Neutropenia -- The addition of VICTRELIS to PR is associated with an additional decrease in hemoglobin concentrations compared to PR alone and/or may result in worsening of neutropenia associated with PR therapy alone. Dose reduction or discontinuation of peginterferon alfa and/or ribavirin may be required. Dose reduction of VICTRELIS (boceprevir) is not recommended. VICTRELIS must not be administered in the absence of PR.

 

Important safety information about VICTRELIS (boceprevir)

 

All contraindications to PR also apply since VICTRELIS must be administered with PR. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with PR is contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; have monthly pregnancy tests; and use two or more forms of effective contraception, including intrauterine devices and barrier methods, during treatment and for at least 6 months after treatment has concluded. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS.

 

VICTRELIS is contraindicated in coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. VICTRELIS also is contraindicated in coadministration with potent CYP3A4/5 inducers, where significantly reduced VICTRELIS plasma concentrations may be associated with reduced efficacy. Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John's Wort (hypericum perforatum), lovastatin, simvastatin, drosperinone, Revatio^® (sildenafil) or Adcirca^® (tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and orally administered midazolam.

 

Complete blood counts (with white blood cell differential counts) must be conducted in all patients prior to initiating combination therapy with VICTRELIS. Complete blood counts should be obtained at treatment weeks 4, 8 and 12, and should be monitored closely at other time points, as clinically appropriate.

 

The most commonly reported adverse reactions (greater than 35 percent) in clinical trials in adult patients receiving the combination of VICTRELIS (boceprevir) with PR were fatigue, anemia, nausea, headache and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates greater than or equal to 5 percent above the rates for PR alone in either clinical study. The incidence of these adverse reactions in previously untreated patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (58 vs. 59 percent), anemia (50 vs. 30 percent), nausea (46 vs. 42 percent) and dysgeusia (35 vs. 16 percent), respectively. The incidence of these adverse reactions in previous treatment-failure patients who were treated with combination therapy with VICTRELIS compared with PR alone were: fatigue (55 vs. 50 percent), anemia (45 vs. 20 percent), nausea (43 vs. 38 percent) and dysgeusia (44 vs. 11 percent), respectively.

 

VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for drug-drug interactions must be considered prior to and during therapy.

 

Please see U.S. prescribing information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

 

About the Study

The primary endpoint of the study was the comparison of SVR in patients who were randomized to receive ribavirin dose reduction or the addition of EPO, and those results were presented at the European Association for the Study of the Liver (EASL) 2012 annual meeting. The rates of SVR were 71 percent for both groups: those patients whose anemia was managed by ribavirin dose reduction (178/249) and those patients whose anemia was managed by the addition of EPO (178/251). The rates of relapse were 10 percent in both groups.

In this study, 687 treatment-naïve adult patients with chronic HCV genotype 1 who had baseline hemoglobin levels at least 12 g/dL for females and at least 13 g/dL for males, but less than or equal to 15 g/dL were enrolled in a randomized, multinational, open-label trial and monitored for the development of anemia. Patients were treated with a 4-week lead-in of peginterferon alfa-2b (1.5 mcg/kg/week) and an investigational dose of weight-based ribavirin (600-1,400 mg/day), followed by the addition of VICTRELIS (boceprevir) (800 mg three times a day) after week 4 for 24 or 44 weeks based on response-guided therapy. Patients with compensated cirrhosis were allowed (METAVIR fibrosis score of F1-F4) provided they had no other concurrent liver diseases. Patients with HIV or hepatitis B virus were excluded.

A total of 500 patients developed anemia, defined by having hemoglobin of approximately less than or equal to 10 g/dL. Patients with anemia were randomized to receive either ribavirin dose reduction (by 200 mg/d [or 400 mg/d if the initial ribavirin dose was 1,400 mg/d]) or the addition of EPO (starting at 40,000 units/week, but could be modified at the investigator's discretion to doses of 20,000 – 60,000 units/week). A secondary method of anemia management, such as the addition of EPO or ribavirin dose reduction was later permitted if a patient's hemoglobin reached less than or equal to 8.5 g/dL. Treatment was discontinued if hemoglobin levels reached less than or equal to 7.5 g/dL.

Impact of timing and magnitude of ribavirin dose reduction on SVR
In the ribavirin dose reduction arm, SVR rates were generally similar regardless of when patients began ribavirin dose reduction, the number of steps of ribavirin dose reduction, or the lowest ribavirin dose of 400 to 1,000 mg/day received for at least 14 days for anemia management. There were few patients, ranging from 3 to 12 in each subgroup, in the ribavirin dose reduction arm who received the lowest ribavirin doses outside the range of 400 to 1,000 mg/day for at least 14 days.

• SVR rates according to the time of the initial ribavirin dose reduction were 70 percent (38/54) at less than or equal to 4 weeks; 64 percent (58/90) from more than 4 to 8 weeks; 79 percent (49/62) from more than 8 to 12 weeks; 82 percent (18/22) from more than 12 to 16 weeks; and 71 percent (15/21) from more than 16 weeks.

• SVR rates according to the number of steps of ribavirin dose reduction

Steps	1	2	3	4	5	6	7
SVR % (n/N)	67 (47/70)	76 (44/58)	80 (20/25)	64 (9/14)	77 (23/30)	69 (24/35)	83 (10/12)

* One step = decrease of 200 mg ribavirin per day for greater than or equal to 3 days

• SVR rates by lowest ribavirin dose received for at least 14 days

Dose (mg/day)	0	200	400	600	800	1000	1200	1400
SVR % (n/N)	92 (11/12)	60 (3/5)	70 (28/40)	75 (58/77)	77 (43/56)	67 (30/45)	36 (4/11)	33 (1/3)

*Lowest ribavirin dose (mg/day) received for at least 14 days during the treatment period based on information in patient diaries.

This sub-analysis included small numbers of patients in some subgroups. Patients were not randomized into subgroups so there could be baseline differences that affected the results.

Impact of HCV-RNA levels at start of anemia management intervention on SVR
The SVR rates for patients with undetectable levels of virus (HCV RNA) at the start of the anemia management intervention were the same – 86 percent – among patients who had ribavirin dose reduction (111/129) and patients who received EPO (107/124). Additionally, the SVR rates for patients with detectable levels of HCV RNA at the start of intervention were the same – 56 percent – among patients who had ribavirin dose reduction (67/120) and patients who received EPO (71/127).

Anemia management interventions in cirrhotic patients
In another sub-analysis of the study, nine percent (60/664) of patients with available central pathology biopsy results were cirrhotic (METAVIR fibrosis score of F4). Of these, 80 percent (48/60) met the protocol definition for anemia and were randomized to one of the two anemia management strategies.

Of the patients requiring an anemia management strategy, the rates of SVR in the ribavirin dose reduction arm were 57 percent (13/23) in cirrhotic patients and 73 percent (162/221) in non-cirrhotic patients, while the rates of SVR in the EPO arm were 64 percent (16/25) in cirrhotic patients and 72 percent (157/217) in non-cirrhotic patients.
A higher percentage of cirrhotic patients received secondary interventions for anemia management than non-cirrhotic patients at 44 percent (21/48) and 26 percent (114/438), respectively.
This sub-analysis was limited by a small sample size of patients with cirrhosis, and the study was not stratified by cirrhotic versus non-cirrhotic patients.

Safety findings
In the sub-analysis evaluating anemia management strategies in cirrhotic patients, the most common adverse events occurring in 25 percent or more of either cirrhotic or non-cirrhotic patients were fatigue, anemia, nausea, diarrhea, dysguesia (bad taste), headache, neutropenia, alopecia, chills, dizziness, decreased appetite, insomnia and influenza-like illness.

Cirrhotic patients were more likely to develop lower platelet counts than non-cirrhotic patients.
Serious adverse events occurred in 20 percent of cirrhotic patients and 12 percent of non-cirrhotic patients. The discontinuation rates due to any adverse event were 17 and 16 percent, respectively. One non-cirrhotic patient who had multiple cardiac risk factors died of sudden cardiac arrest 23 days after discontinuing study drugs.

Merck's global commitment to advancing hepatitis therapy
Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies with VICTRELIS, extensive research efforts are underway to develop additional oral therapies for viral hepatitis treatment.

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement
This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that all of the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2011 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).
 

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Please see Prescribing Information for VICTRELIS^® (boceprevir) at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf and Medication Guide for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_mg.pdf.
¹ SVR, the protocol specified primary efficacy endpoint of the study, is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment in all randomized patients treated with any study medication. Per protocol, if a patient did not have a 24-week post-treatment assessment, the patient’s 12-week post-treatment assessment was utilized.

VICTRELIS™is a trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.

Revatio^® and Adcirca^® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA.

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ITPA Deficiency Cuts Anemia Risk, Even on Boceprevir

Elsevier Global Medical News

MAY 2 0 1 2 • G I & H E PATOLOGY NEWS
May Newsletter

BY SUSAN LONDON
Elsevier Global Medical News

ITPA Deficiency Cuts Anemia Risk, Even on Boceprevir
SAN FRANCISCO – Patients who have chronic hepatitis C and a deficiency of inosine triphosphatase are less likely to develop anemia on ribavirin containing herapy, whether or not they receive additional boceprevir therapy,findings from a retrospective study suggest.

The study included data on 908 patients participating in a pair of randomized trials that tested the addition of boceprevir to peginterferon and ribavirin.

Lead author Dr. Mark S. Sulkowski of the Johns Hopkins University in Baltimore reported the results in a poster session at the annual meeting of the American Association for the Study of Liver Diseases.

“The clinical implications are that if you had a patient whom you knew was deficient [in inosine triphosphatase], you would anticipate less [risk of] anemia and the ability to give more ribavirin,” he commented. “And perhaps you would treat them differently. That’s speculation,as this test is not commercially available.”

About one-third of the patients had low activity of inosine triphosphatase (ITPA), an enzyme that degrades inosine triphosphate. Inosine triphosphate protects red blood cells from ribavirin-induced hemolysis (Gastroenterology 2011; 140:1314-21).

“The data show it’s all due to the impact of ITPA activity deficiency on ribavirin anemia,” Dr. Sulkowski noted in an interview. On average, anemia develops in 55% of patients with normal ITPA activity and in 41% of those with low ITPA activity, a pattern that was consistent across treatment arms.

“Since this is a multifactorial anemia – interferon bone marrow suppression,boceprevir likely through an impact on bone marrow, and ribavirin hemolysis – it’s [affecting] only one of the components,” he said.

This is not the first study to show that ITPA deficiency protects against ribavirin- induced anemia. The new finding here is that the same is seen in patients also receiving boceprevir – which typically improves SVR rates when added to interferon and ribavirin, but also leads to an additional drop in hemoglobin.

Patients with low ITPA activity were less likely to need a ribavirin dose reduction or to receive erythropoietin. Also, they tended to have a higher rate of sustained virologic response.

The findings also point to several possible areas of future research and clinical application, according to Dr. Sulkowski.

“One of them is that with any combination of hepatitis C treatment that includes ribavirin, this is likely to play a role: people who are deficient or have low ITPA activity will have less hemolytic anemia and therefore tolerate ribavirin a bit better,” he said.

“The other is that if you could find a way pharmacologically to make people deficient in ITPA, assuming it’s safe – and we think it’s safe because these one-third of patients are fine, this is a natural variant then you could potentially make ribavirin a bit safer by coadministering that drug,” he added.

In the study, the investigators analyzed data from two randomized boceprevir trials among patients with chronic hepatitis C having viral genotype 1: the SPRINT-2 trial in treatment-naive patients and the RESPOND-2 trial in patients who had had a failure of previous therapy.Both trials had a 4-week lead-in period during which all patients received only peginterferon plus ribavirin. Thereafter,patients were assigned to continue peginterferon plus ribavirin alone, or with the addition of boceprevir for a shorter or longer duration, with treatment ending by 48 weeks.

Study results were based on a total of 650 patients from the SPRINT-2 trial and 258 patients from the RESPOND-2 trial who had samples for ITPA assessment.

Overall, 32% had low ITPA activity. Patients were less likely to develop anemia during the lead-in period if they had low ITPA activity (12%) than if they had normal ITPA activity (48%). In addition, within each treatment arm, patients were less likely to develop anemia at any time during treatment if they had low ITPA activity. Anemia occurred in 41% of those with low ITPA activity and in 55% of those with normal activity.

Ribavirin dose was reduced or erythropoietin was given to 38% of patients with low ITPA activity and to 49% of patients with normal ITPA activity.
Finally, within each treatment arm, patients with low ITPA activity tended to be more likely to have a sustained virologic response. A sustained virologic response was seen in 65% of patients with low ITPA activity and 59% with normal ITPA activity.

Dr. Sulkowski reported that he is an advisor to or reviewer for Pfizer, and is a consultant to and receives grant or research support from Roche, Merck, Abbott, Vertex,Tibotec, Boehringer Ingelheim Pharmaceuticals,Gilead, Bristol-Myers Squibb,and Pharmasset.

http://www.gastro.org/journals-publications/gi-hepatology-news/GI_-_Hepatology_News_-_May_2012.pdf

Hepatitis News Ticker: Anemia During HCV Therapy - INCIVEK and VICTRELIS

 “Systems,” by Dan Beckemeyer

HCV Abstract Corner

CAP Hepatitis C Literature Review 

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 

Anemia During HCV Therapy 

Anemia and Hepatitis C Treatment

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.

Continue reading "Anemia and Hepatitis C Treatment"

The Outcomes and Management of Anemia in the Phase III Trials of Boceprevir and Telaprevir

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

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

Ribavirin Rather than PEG-interferon Pharmacodynamics Predict Nonresponse to Antiviral Therapy in Naive Chronic Hepatitis C Patients

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

Docs Are Surrendering To Generics: Survey

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

Valentine's Day Is The Worst Time To Kiss, Says Loyola Infectious Disease Specialist 

Released: 2/1/2012 10:30 AM EST
Source: Loyola University Health System

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.

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.”

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!”

Off The Cuff 

Source Medgadget

Magic Mirror for Seeing Your Insides Gets an Upgrade

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

FYI


Dr. Paul Kwo on Hepatitis C Screening During Routine Colonoscopy 

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

Posted by Rebecca Hersher

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.”

Scripps Health ;IL28B Genetic Testing to Hepatitis C Patients Now Available

Scripps Pioneers Individualized Medicine by Offering Genetic Testing to Hepatitis C Patients
Individualized Therapies Now Available for Drug Treatment of Hepatitis C

"Later this year, a second test will be available that will accurately predict anemia in hepatitis C patients taking the pegylated interferon and ribavirin drug combination. Anemia is one of the most common side effects of the regimen. This will allow doctors to modify the therapy before starting the regimen to prevent patients from developing this problematic side effect."

SAN DIEGO, Feb. 25, 2011 (GLOBE NEWSWIRE) -- Scripps Health is one of the first health systems in the United States to offer genetic testing as part of its care for hepatitis C patients planning to undergo drug treatment.

The tests offer hope to the more than 4 million patients diagnosed annually in the U.S. with hepatitis C and could spare them from taking interferon, which is commonly prescribed. Interferon causes flu-like symptoms as a side effect and costs more than $50,000 annually. Instead, the genetic test determines whether patients have a common gene variant that predicts a favorable cure rate if they are treated with the drug combination therapy of pegylated interferon and ribavirin.

A manuscript describing this approach to treatment, authored by Paul J. Pockros, MD, clinical director of research at the Scripps Translational Science Institute, head of the Division of Gastroenterology and Hepatology and director of the Liver Disease Center at Scripps Clinic, will be published in the journal Drugs in March.

"This is a huge step forward in the movement toward individualized medicine," said Dr. Pockros, "As a physician, knowing what drug therapies will have benefit and which ones won't based on a patient's IL28B genotype is significant because we are able to be more targeted in our approach to treatment."

This is the first of numerous genetic tests that will accurately give doctors vastly improved data, leading to better prescription of drug treatments. Later this year, a second test will be available that will accurately predict anemia in hepatitis C patients taking the pegylated interferon and ribavirin drug combination. Anemia is one of the most common side effects of the regimen. This will allow doctors to modify the therapy before starting the regimen to prevent patients from developing this problematic side effect.

Genetic testing for hepatitis C patients carries significant implications for patient care, as there are more than 4 million infected people in the United States, most of them undiagnosed and untreated.

Scripps Clinic now routinely orders IL28B genotyping on all patients with Hepatitis C who are potential candidates for anti-viral therapy. If the patients have a favorable IL28B genotype and advanced fibrosis on liver biopsy, doctors can initiate therapy with the current standard of care. If patients have a less favorable genotype or they have mild fibrosis, doctors can recommend waiting for FDA approval of direct acting antiviral drugs to improve their chances of response.
Currently, LabCorps Diagnostics is performing the IL28B testing for Scripps patients, a procedure covered by most insurance plans. The results are transmitted to the treating physician in about one week and the treatment choice is tailored based on the patient's likelihood to have a favorable response.

The hepatitis C genetic testing is the latest example of Scripps' leadership in individualized medicine. Scripps doctors were the first to use genetic testing for cardiovascular patients planning to undergo elective stent procedures to determine if they have one or more of the common gene variants linked to an inability to metabolize the anti-clotting drug Plavix (clopidrogel). Plavix is the second-most commonly prescribed drug in the United States and is given to most patients after they receive coronary stents.

ABOUT SCRIPPS HEALTH
Founded in 1924 by philanthropist Ellen Browning Scripps, Scripps Health is a $2.3 billion nonprofit community health system based in San Diego, Calif. Scripps treats a half-million patients annually through the dedication of 2,500 affiliated physicians and 13,000 employees among its five acute-care hospital campuses, home health care services, and an ambulatory care network of physician offices and 22 outpatient centers and clinics. Scripps has been recognized by Thomson Reuters as one of the Top 10 health systems in the nation for quality care. Scripps is also at the forefront of clinical research, genomic medicine, wireless health and graduate medical education. With three highly respected graduate medical education programs, Scripps is a longstanding member of the Association of American Medical Colleges. More information can be found at www.scripps.org.

This information was brought to you by Cision http://www.cisionwire.com

Emerging Drug Class May Enhance Red Blood Cell Production in Anemic Patients

Emerging Drug Class May Enhance Red Blood Cell Production in Anemic Patients

Released: 12/22/2010 11:25 AM EST

Embargo expired: 12/22/2010 2:00 PM EST
Source: Whitehead Institute for Biomedical Research


FINDINGS: By determining how corticosteroids act to increase production of red blood cell progenitors, Whitehead Institute researchers have identified a class of drugs that may be beneficial in treating some erythropoietin-resistant anemias. One such anemia is Diamond-Blackfan anemia (DBA), which is frequently treated with corticosteroids, despite their severe side-effects.

The identified class of drugs may be able to treat other anemias, including those resulting from trauma, sepsis, malaria, kidney dialysis, and chemotherapy.

RELEVANCE: Some common anemias can be treated with the hormone erythropoietin (EPO), which stimulates red blood-cell production. However, certain anemias, including DBA, do not respond to EPO, creating a large unmet medical need.

Newswise — By determining how corticosteroids act to promote red blood cell progenitor formation, Whitehead Institute researchers have identified a class of drugs that may be beneficial in anemias, including those resulting from trauma, sepsis, malaria, kidney dialysis, and chemotherapy.

Anemia occurs due to a breakdown in erythropoiesis, the multi-step process that creates red blood cells. Some common anemias can be treated with a recombinant form of the hormone erythropoietin (EPO), which normally stimulates red blood-cell production at a fairly early stage of erythropoiesis. However, certain anemias fail to respond to EPO, creating a large unmet medical need. In the case of Diamond Blackfan anemia (DBA), patients lack a sufficient number of EPO-responsive cells.

Instead, corticosteroids such as prednisone or prednisolone are used to treat DBA, although it has been unclear exactly how these agents affect erythropoiesis. To see how corticosteroids are able to increase red blood cell counts, Johan Flygare, a postdoctoral researcher in the lab of Whitehead Institute Founding Member Harvey Lodish, purified two progenitors of red blood cells, called burst forming unit-erythroids (BFU-Es) and colony forming unit-erythroids (CFU-Es), from mouse fetal liver cells. During erythropoiesis, BFU-Es produce CFU-Es, which are then stimulated by EPO to generate the pro-erythroblasts that eventually become red blood cells.

By dividing numerous times before maturing, both BFU-Es and CFU-Es have a limited ability to self-renew. When Flygare exposed BFU-Es and CFU-Es in vitro to a corticosteroid, only the BFU-Es responded--dividing 13 times instead of the usual 9 times before maturing into CFU-Es. These additional cell divisions ultimately led to a 13-fold increase in red blood-cell production.Flygare identified 83 genes in BFU-Es that are stimulated by the corticosteroid, and he examined the promoters that facilitate those genes’ transcription. The promoters appeared to have binding sites for a transcription factor, called hypoxia-induced factor 1-alpha (HIF1-alpha), that is activated when an organism is deprived of oxygen. To prolong the 83 genes’ promotion by HIF1-alpha, Flygare used a class of drugs known as prolyl hydroxylase inhibitors (PHIs), which extends HIF1-alpha’s effectiveness. PHIs have also been used in early-stage clinical trials to increase EPO production.

When Flygare added both a corticosteroid and a PHI to BFU-Es in culture, the cells produced 300 times more red blood cells than did cells without exposure to the drugs. Flygare repeated the experiment with adult human BFU-Es, and found that a corticosteroid plus a PHI generated 10 times more red blood cells than BFU-Es exposed to a corticosteroid alone.Flygare hopes this research eventually leads to improved treatment for DBA patients who currently suffer from a host of corticosteroid-induced side effects, including decreased bone density, immunosuppression, stunted growth, and cataracts. “If you could lower the dose of steroids so DBA patients would get just a little bit, and then add on this kind of drug, like a PHI, that would boost the effect, maybe you could get around the steroids’ side effects,” says Flygare. “That would be good.”

This new approach to increasing erythropoiesis by extending the self-renewal of BFU-Es—resulting in creation of more EPO-responsive cells—could lead to novel therapies for other anemias. “There are a number of anemias that are much more prevalent than DBA and that cannot be treated with EPO, either, such as anemias from trauma, sepsis, malaria, and anemia in kidney dialysis patients,” says Lodish, who is also a professor of biology and bioengineering at MIT. “Whether these treatments will work in those conditions remains to be seen.”This research was supported by the Diamond Blackfan Anemia Foundation, the Swedish Research Council, Maja och Hjalmar Leanders Stiftelse, The Sweden-America Foundation, and the National Institutes of Health (NIH).Written by Nicole Giese* * *Harvey Lodish’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology and a professor of bioengineering at Massachusetts Institute of Technology.

* * *Full Citations:
“HIF-1 Alpha synergizes with glucocorticoids to promote BFU-E progenitor self-renewal”Blood, published online the week of December 22, 2010Johan Flygare (1), Violeta Rayon Estrada (1), Chanseok Shin (1, 2), Sumeet Gupta (1), and Harvey F. Lodish (1, 3, 4).1. Whitehead Institute for Biomedical Research, Cambridge, MA 021422. Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea3. Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, MA

http://www.newswise.com/articles/emerging-drug-class-may-enhance-red-blood-cell-production-in-anemic-patients