Neutropenia-Lymphocyte count associated with infection risk during HCV interferon treatment

Lymphocyte count associated with infection risk during interferon treatment
Melia M. Clin Infect Dis. 2014;doi:10.1093/cid/ciu009.

Adults with hepatitis C who were treated with pegylated interferon and ribavirin for up to 48 weeks commonly experienced moderate, severe or life-threatening infections, according to a report in Clinical Infectious Diseases.

The nadir lymphocyte count, but not the nadir neutrophil count, was associated with the increased risk for infections in the Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study.

“While the risk of infection associated with severe neutropenia due to chemotherapy among cancer patients and recipients of hematopoietic cell transplants is well-established, most studies have not demonstrated any increased risk among patients who develop neutropenia while receiving [pegylated interferon],” the researchers wrote. “Nevertheless, up to 23% of patients develop acute infections during HCV treatment.”

Patients in the IDEAL study were randomly assigned to varying doses of pegylated interferon with ribavirin for chronic HCV treatment. In this study, the investigators from evaluated the risk for infection among patients with myelosuppression, a common adverse effect of pegylated interferon treatment.

The IDEAL study included 3,070 treatment-naïve patients. Among those, 581 (19%) patients experienced moderate, severe or life-threatening infections, determined by the investigator. In a logistic regression model, female gender, history of depression and nadir on-treatment absolute lymphocyte count were associated with moderate, severe or life-threatening infections. After adjustment, pegylated interferon type (alfa-2a vs. alfa-2b) and nadir absolute neutrophil count were not associated with moderate, severe or life-threatening infections.

“This observation has important implications for the management of patients treated with [pegylated interferon/ribavirin] alone or in combination with other agents,” the researchers wrote. “While further research is needed to confirm this observation, clinicians should carefully monitor the [absolute lymphocyte count] in addition to the [absolute neutrophil count] for patients receiving HCV therapy with [pegylated interferon and/or ribavirin].”

Disclosure: See study manuscript for disclosure information.

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Infections Not Tied to Neutropenia in HCV/HIV Patients on PegIFN/RBV

Infections Not Tied to Neutropenia in HCV/HIV Patients on PegIFN/RBV

Author: Mark Mascolini

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02 September 2013

 

Neutropenia caused by treatment with pegylated interferon and ribavirin (PegIFN/RBV) was not related to severe or nonsevere infections in a study of 418 HCV/HIV-coinfected people in Madrid.

Neutropenia (low white blood cell levels) is a common complication of treatment with PegIFN/RBV for hepatitis C virus infection. Because research had not addressed whether this neutropenia promotes infection in people with HCV and HIV, researchers in Madrid conducted this prospective cohort study from 2000 through 2012.

The investigators defined serious infections as those requiring hospital admission, requiring discontinuation of PegIFN/RBV, or causing death. They defined severe neutropenia as a white cell count below 500 cells/μL, while nonsevere neutropenia meant a count between 500 and 1500 cells/μL.

The study involved 418 people receiving PegIFN/RBV for 3928 person-weeks. The researchers recorded 149 infections in 123 people (29%) for an infection incidence of 3.8 per 100 person-weeks of therapy, meaning almost 4 of every 100 people got an infection every week. Almost half of infections (47%) involved the upper respiratory tract and were minor.

To identify factors associated with infection, the researchers conducted a logistic regression analysis adjusted for age, gender, CD4 count, AIDS, antiretroviral therapy, cirrhosis, neutrophil count, type of PegIFN, and granulocyte colony-stimulating factor use. None of these factors was independently associated with infection.

Twenty study participants (4.8%) had a serious infection. Serious infections were more frequent in people with severe neutropenia (8.6%) than in those with nonsevere neutropenia (4.8%) or without neutropenia (3.6%), but these differences were not statistically significant (P = 0.28). Multivariate analysis identified no factors independently associated with increased risk of serious infection.

“In this large prospective cohort of HIV/HCV-coinfected patients treated with peg-IFN plus RBV,” the researchers conclude, “serious infections were uncommon, nonfatal, and unrelated to peg-IFN-induced severe neutropenia.”

Source: Sergio Serrano-Villar, Carmen Quereda, Ana Moreno, María Jesús Pérez-Elías, José Luis Casado, Ana Royuela, Fernando Dronda, Enrique Navas, José Manuel Hermida, Santiago Moreno. Neutropenia during therapy with peginterferon and ribavirin in HIV-infected subjects with chronic hepatitis C and the risk of infections. Clinical Infectious Diseases. 2013; 57: 458-464.

For the study abstract

(Downloading the complete article requires a subscription to Clinical Infectious Diseases or an online payment; the abstract is free.)

 

http://www.iasociety.org/Article.aspx?elementId=15425

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.

Contact:

Media Contacts:
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Hepatitis C: White Blood Count During Therapy

What Are The Tests Given Prior To HCV Therapy:

Thyroid function test, hemoglobin, complete and differential white blood cell counts, platelet counts and blood chemistries including liver function tests. A pregnancy test, chest roentgenogram and ECG should also be performed prior to initiating interferon therapy. Also an eye exam should be preformed.

What Are The Hematologic Side Effects Of HCV Therapy

The side effects from interferon and ribavirin therapy often lead to lowered dosages or even discontinuation of therapy. Ribavirin causes a dosage-dependent, hemolytic anemia, and interferon can suppress bone marrow production of red blood cells.

See Related Information Anemia During HCV Treatment

Interferon suppresses bone marrow production of leukocytes, which leads to a drop in the white blood count or neutropenia in approximately 20% of treated patients. A certain type of white blood cell called "neutrophils" are important in fighting bacterial infections.

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What Causes A Low Neutrophil Count?
Neutrophils die continuously from age or from fighting infections, and your bone marrow must make new neutrophils to replace them. When something reduces production of neutrophils in your bone marrow, the neutrophil count will drop and may become dangerously low. Prescription medications or HCV antiviral drugs such as interferon can cause neutropenia. In almost all cases, drug-induced neutropenia (low white count) resolves after the agent is stopped or its dosage is reduced.

What Is A Normal White Count ?
Normal Adult Range: 3.8 - 10.8 thous/mcl
Optimal Adult Reading: 7.3
Higher ranges are found in children, newborns and infants.

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What are neutrophils?
Neutrophils are a major part of your body’s defense against bacterial infections. When the WBC is low, there may not be enough neutrophils to defend you against bacterial infections. Neutrophils are made in the bone marrow and circulate in the bloodstream. Neutrophils move out of the blood vessels into the infected tissue to attack the bacteria. The pus in a boil (abscess) is made up mostly of neutrophils. Normally a serious bacterial infection causes the body to produce an increased number of neutrophils, resulting in a higher than normal WBC.

What Do Physicians Consider A Low Neutrophil Count Or (absolute neutrophil count = (ANC)

Neutropenia is a common reason for dose adjustment during HCV therapy, if the white count or the neutrophil count gets to be very low, typically your doctor may adjust down the interferon dose.
Physicians like to keep the neutrophil count (absolute neutrophil count = (ANC) above 750, patients do not typically develop infections. However, if neutrophil counts go below 500/µL interferon is suspended.

Physicians sometimes use a drug called GM-CSF or Neupogen to keep up the white count. Neupogen is a drug that is used primarily for cancer patients receiving chemotherapy. It is effective in getting the bone marrow to make more white cells. Like interferon, it has to be injected.

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How Can I Figure Out My Absolute Neutrophil Count (ANC)?
Neutrophil% x White Blood Cell = Absolute Neutrophil Count

For example, if a person's white blood cell count were 6,000 cells, and neutrophils made up 50% of those, that person's absolute neutrophil count would be 3,000.

From The Cleveland Clinic:

Hepatitis C Management
Ask The Experts

Question:
In an HCV-infected patient with neutropenia who is receiving pegylated interferon and ribavirin, what is the recommended absolute neutrophil count (ANC) target range when treating with filgrastim (Neupogen)?

At what absolute neutrophil count =ANC value should filgrastim therapy be initiated, and what is the suggested dosage?

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Answer:

The clinical implication of neutropenia during HCV therapy remains controversial. In one study of 119 HCV patients who were treated with the combination therapy, bacterial infections were not associated with severe neutropenia. The current recommended dose-reduction threshold for neutropenia is an ANC of less than 750. The safety and efficacy of filgrastim for managing interferon-related neutropenia in patients with HCV has not been established, and its use in this specific situation is not FDA-approved. Small-scale studies of filgrastim 300 µg weekly to 300 µg thrice weekly have suggested efficacy with relative safety.
Clinicians who decide to use filgrastim should carefully monitor white blood cell counts after filgrastim and should use the lowest effective dose.

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White Blood Cell Chases Bacteria
It's dinner time for this white blood cell. White blood cells are cells of the immune system defending the body against both infectious disease and foreign materials.

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What are the most serious side effects of PEGASYS and COPEGUS?

Serious side effects are:
Mental health problems (such as depression, thoughts about suicide, suicide attempts and relapse of drug abuse or drug overdose, all of which can lead to death. Other problems include thoughts of homicide or hurting other people, irritability, anxiety, aggressiveness, bipolar disorders, mania, and hallucinations)
Blood problems (like a drop in blood cells leading to increased risk for infections, bleeding and/or heart or circulatory problems). Low levels of red blood cells can cause death in patients taking COPEGUS. Most blood counts may be reduced including white blood cell, red blood cell, platelets, hemoglobin, neutrophil, and lymphocyte counts.
Other blood disorders
Problems with pregnancy
Lung problems (like trouble breathing, pneumonia, inflammation of lung tissue, and high lung blood pressure), sometimes requiring a machine to breathe for you and/or causing death
Eye problems (blurred, loss of vision, and retinal detachment)
Autoimmune problems (sarcoidosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and thyroid problems, such as hyperthyroidism and hypothyroidism)
Heart problems (including high or low blood pressure, chest pain, fast heart rate, and heart attacks) which can lead to death
Stomach pain (stomach or corneal ulcers)
Rash with fever or blisters
Weakness, loss of coordination, numbness, and difficulty speaking due to stroke, including patients with no known risk for stroke
Liver problems (rarely, liver function worsens) including an increased chance of liver failure in patients with cirrhosis. Patients with both the hepatitis C virus and HIV have an increased chance of liver failure during PEGASYS treatment. Change in a blood test that measures liver inflammation occurs more often in patients with hepatitis B. If you have a rise in this blood test you may need to be watched more closely with additional blood tests. Severe liver damage can lead to death
Colitis (inflammation of the colon, which can cause abdominal pain, bloody diarrhea, and fever) which can lead to death
Inflammation of the pancreas, muscles, and bile ducts which can lead to death
Blood sugar problems such as high or low blood sugar and diabetes
Bacterial, viral, fungal infections (such as in the blood, bones, heart, kidneys and lungs) which can lead to death

What are the most common side effects of PEGASYS and COPEGUS?
The most common side effects are:
Flu-like symptoms (including fever, chills, muscle aches, joint pain, headaches, tiredness)
Upset stomach (like nausea, vomiting, taste changes, diarrhea)
Skin problems (like rash, dry or itchy skin, or redness and swelling at injection site)
Hair thinning or loss (temporary)
Mental health problems (such as depression, difficulty sleeping, irritability, and anxiety)
Anorexia or loss of appetite leading to weight loss
Dehydration
Tell your doctor immediately if you think you or your partner may be pregnant or if any of these symptoms occur.

Risk factors for infection during treatment for chronic Hep C

Neutropenia during treatment with peginterferon alfa and ribavirin for chronic hepatitis C virus infection is a common cause of dose reductions of peginterferon alfa.

These reductions are performed to prevent bacterial and fungal infections, which are common during hepatitis C virus treatment, and can be attributed to neutropenia.

Dr Robert de Knegt and colleagues from the Netherlands investigated the occurrence of infections and their relation to neutropenia, and identified potential risk factors for infections during hepatitis C virus treatment.

In this single-center cohort study, 2,876 visits of 321 patients treated with peginterferon alfa and ribavirin were evaluated for neutropenia, infections, dose reductions, and potential risk factors for infection during hepatitis C treatment.

The baseline mean absolute neutrophil count (ANC) was 3420 cells/μL, and 16 patients had a baseline ANC of less than 1500 cells/μL.

14% of infections were defined as severe
Hepatology
The research team observed neutropenia, defined as ANC less than 750 cells/μL, in 30% of patients, and ANC less than 375/μL in 5% of patients.

The research team found that 22% had infections.

The team noted that 14% of infections were defined as severe.

Infections were not correlated with neutropenia during treatment.

The team observed that dose reductions did not lead to a decrease in infection rate.

Multivariate logistic regression analysis revealed that age over 55 years, and baseline hyperglycemia were associated with an increased risk of infection during hepatitis C virus treatment.

Cirrhosis and chronic obstructive pulmonary disease were not risk factors for infection.

Dr de Knegt's team concluded, "Bacterial infections during treatment with peginterferon alfa and ribavirin are not associated with neutropenia."

"Older patients and patients with poorly controlled diabetes mellitus have a greater risk of developing infections during hepatitis C virus treatment."

http://www.gastrohep.com/news/news.asp?id=107604

HCV Treatment and Neutropenia(low white count)

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White blood counts: What is to low ?

Combination therapy with interferon and ribavirin commonly drives down the white count and especially a certain type of white cell called neutrophils that are important in fighting bacterial infections. It is important for people to appreciate that it is the interferon part of the treatment that really drives down the white count. It is possible that the (ribavirin) part contributes, but studies show that when they use interferon alone, they see the same problem. As a result, if the white count or the neutrophil count gets to be very low, doctors might typically adjust down the interferon dose and not the Ribavarin dose.

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With time and experience, studies have showed that people treating hepatitis C can tolerate a lower white count on treatment than originally thought. If they are able to keep the neutrophil count (ANC) above 750, people do not typically develop infections.

Also, doctors sometimes use a second drug called GM-CSF or Neupogen to keep up the white count. Neupogen is a drug that is used primarily for cancer patients receiving chemotherapy. It is effective in getting the bone marrow to make more white cells. Like interferon, it has to be injected.

How To Figure Out If Your Neutrophil Count

Neutrophil% x White Blood Cell = Absolute Neutrophil Count

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For example, if a person's white blood cell count were 6,000 cells, and neutrophils made up 50% of those, that person's absolute neutrophil count would be 3,000.

,

A normal range for neutrophil% is between 33% and 72%. This makes the normal range for the ANC between 1500 and 7200. Since every individual is unique, you should consult your physician or nurse if you have questions concerning your white blood cell count and ANC.

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If you’re total white count is 1.0 (1000) or below then your neutrophils would be around 500… to low to continue therapy. Although treatment is not always discontinued (in some cases) the dose is cut back until the white count increases.

Here Is The Latest Abstract

Hepatology. 2010 Oct;52(4):1225-31.

Risk factors for infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C. ,Roomer R, Hansen BE, Janssen HL, de Knegt RJ.
Departments of Gastroenterology and Hepatology, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Abstract

Neutropenia During HCV Treatment

Neutropenia during treatment with peginterferon alfa and ribavirin for chronic hepatitis C virus (HCV) infection is a common cause of dose reductions of peginterferon alfa. These reductions are performed to prevent bacterial and fungal infections, which are common during HCV treatment and can be attributed to neutropenia. .

What Are The Aims Of This Study ?

The aims of this study were to investigate the occurrence of infections and their relation to neutropenia and to identify potential risk factors for infections during HCV treatment.

How Many People In The Study ?

In this single-center cohort study, 2,876 visits of 321 patients treated with peginterferon alfa and ribavirin were evaluated for neutropenia, infections, dose reductions, and potential risk factors for infection during HCV treatment.

The baseline mean absolute neutrophil count (ANC) was 3,420 cells/μL, and 16 patients had a baseline ANC of less then1,500> .

How Many People Had Infections ?

Ninety-six infections were observed in 70 patients (21.8%).

Thirteen infections (13.5%) were defined as severe.

Infections were not correlated with neutropenia during treatment.

Did Dose Reductions Decrease Rate Of Infection?

Dose reductions did not lead to a decrease in infection rate. Multivariate logistic regression analysis revealed that age >55 years (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.19-3.56, P = 0.01) and baseline hyperglycemia (OR 2.17, 95% CI 1.15-4.10, P = 0.016) were associated with an increased risk of infection during HCV treatment.

Did Cirrhosis and COPD Have Risk Factors ?

Cirrhosis and chronic obstructive pulmonary disease were not risk factors for infection.

Was Infection Associated With Treatment and Low White Count ?

Conclusion:

Bacterial infections during treatment with peginterferon alfa and ribavirin are not associated with neutropenia. Older patients and patients with poorly controlled diabetes mellitus have a greater risk of developing infections during HCV treatment. (HEPATOLOGY 2010).
PMID: 20830784 [PubMed - in process]LinkOut - more resourcesk

Bacterial Infections and Low White Count During Treatment

White blood cell:

One of the cells the body makes to help fight infections. There are several types of white blood cells (leukocytes). The two most common types are the lymphocytes and neutrophils (also called polymorphonuclear leukocytes, PMNs, or "polys").

Lymphocytes are made in lymphoid tissue in the spleen, lymph nodes, and thymus gland. There are different kinds of lymphocytes. Lymphocytes identify foreign substances from germs (bacteria or viruses) in the body and produce antibodies and cells that specifically target them. It takes from several days to weeks for lymphocytes to recognize and attack a new foreign substance.

Neutrophils are also major players in the body's defense against bacterial infections. Neutrophils are made in the bone marrow and circulate in the bloodstream. Neutrophils move out of the blood vessels into the infected tissue to attack the bacteria. The pus in a boil (an abscess) is made up largely of neutrophils. Normally a serious bacterial infection causes the body to produce an increased number of neutrophils, resulting in a higher than normal white blood cell count (WBC). When the WBC is low, there may not be enough neutrophils to defend against bacterial infections.

The white blood cell count is done by counting the number of white blood cells in a sample of blood. A normal WBC is in the range of 4,000 to 11,000 cells per microliter. A low WBC is called leukopenia. A high WBC is termed leukocytosis.

A normal absolute neutrophil count (ANC) is in the range of 1,500 to 8,000 cells per microliter. If the ANC is below 500 for an extended period of time, the risk of serious bacterial infection may increase significantly. A low neutrophil count is called neutropenia.

Source

Sep 17, 2009 —
SOURCE: Digestive Diseases and SciencesReduction in Neutrophil Count During Hepatitis C Treatment:

Drug Toxicity or Predictor of Good Response?

BACKGROUND:
Bone marrow suppression is a well-recognized toxicity of the treatment of hepatitis C virus (HCV). Reduction of the peginterferon dose because of neutropenia is common in clinical practice. However, reduction of peginterferon dose during the first weeks of HCV treatment is associated with failure to achieve sustained virological response. AIMS: The objective of this study is to investigate whether the fall of neutrophil count during hepatitis C treatment is associated with achieving sustained virological response.

METHODS:
We performed an observational study of patients who completed peginterferon and ribavirin treatment in an Infectious Diseases Department in Manchester, UK.

RESULTS:Of the 74 patients included in the analysis, 78% had genotype 2 or 3 hepatitis C and 15% had liver cirrhosis. Sustained virological response was achieved in 78% of patients. On univariate analysis, factors related to achieving sustained virological response were younger age, genotype 2 or 3, baseline neutrophil count, and fall of neutrophil count during treatment. Multivariate analysis showed baseline neutrophil count>3.5 x 10(3) cells/mm(3) [odds ratio (OR) 5.7; 95% confidence interval (CI) 1.24-26.3] and a reduction of neutrophil count>60% (OR 4.5; 95% CI 1.03-19.9) to be independently associated with achieving sustained virological response. Neutropenia was not associated with an increased risk of infections.

CONCLUSIONS:In this observational study, higher baseline neutrophil count and fall of neutrophil count during the treatment of hepatitis C was associated with achieving sustained virological response. These findings could have important implications for the monitoring and management of HCV treatment with peginterferon if they are confirmed in other studies.

NAMENEUTS (Neutrophils)NORMAL RANGE2.2-8.6 K/µl
DEFINITIONThese are WBC that play a key role in inflammation, allergic reactions, pus formation, and in destroying bacteria and parasites.

EXPLANATION OF TESTRESULT
Low neutrophil can mean infection or inflammation. Interferon treatment is associated with low neutrophil levels. Therefore, you must have normal levels of neutrophils to start interferon.

Source

Low weight predicts neutropenia and peginterferon alfa-2a dose reductions during treatment for chronic hepatitis C

Y. Rotman1,2,4, L. Katz3, M. Cohen1,2,4, O. Cohen-Ezra1, V. Manhaim1, M. Braun1,4, Z. Ben-Ari1,4, R. Tur-Kaspa1,3,4
Article first published online: 11 FEB 2009DOI: 10.1111/j.1365-2893.2009.01079.x

Keywords:bone marrow depression;chronic hepatitis C;neutropenia;pegylated interferon alfa-2a;side-effects;weightSummary.

Treatment-induced neutropenia frequently complicates the treatment course of patients treated with pegylated interferon alfa and ribavirin for chronic hepatitis C.

We investigated the effect of weight on the risk for dose reductions caused by neutropenia in patients treated with a weight-independent dose of peginterferon alfa-2a.

We retrospectively analysed single centre data for 172 patients enrolled in a multi-centre, open-label trial of peginterferon alfa-2a and ribavirin for chronic hepatitis C.

Low body weight was significantly associated with dose reductions due to neutropenia.

Patients weighing less than 62 kg had a 35% risk for significant neutropenia as opposed to a 12% risk for heavier patients (P = 0.001), and this side-effect occurred earlier during treatment. Low weight was an independent risk factor by multivariate analysis (hazard ratio 0.956/kg).

The risk for treatment-induced neutropenia was associated with body surface area more than with the body mass index. In conclusion, a low pre-treatment weight strongly predicts the need for peginterferon alfa-2a dose reductions. This apparently reflects overall body size more than body fat content. It is prudent to frequently monitor blood counts for smaller-sized patients, especially during the first weeks of treatment.

Source

Diagnosing Neutropenia During Chemo (Not HCV Treatment)

Neutropenia can be a serious side effect of treatment, so your doctor will carefully monitor your blood cell counts during treatment. A complete blood count (CBC) is a blood test that measures the levels of these cells in your blood. To diagnose neutropenia, your doctor will evaluate the absolute neutrophil count (ANC) portion of the CBC. The result of the ANC dictates your risk of infection and what treatment may be necessary to prevent or treat existing infection.
When discussing your CBC results, your doctor may talk about specific numbers in relation to your results. Of course, he or she will explain them in detail, but the summary below will help you get see the "bigger picture" in relation to ANC values:

Normal ANC Values: Normal ANC values range from 2,500 to 6,000 neutrophils per cubic millimeter. Ranges vary on a number of factors, from someone just getting over being sick; the presence of infection, diseases and other conditions that may influence count; and even race.

Mild Neutropenia:

Once ANC counts drop to 1,000-1,500, this is considered to be mild neutropenia. If you have mild neutropenia, you aren't at a great risk of developing an infection, but your doctor will probably instruct you to look for any signs of infections and report back any changes.

Moderate Neutropenia:

Moderate Neutropenia occurs when ANC levels are between 500-1,000. If you have moderate neutropenia, then your risk of developing infection is moderate. If you develop symptoms of infection, like fever, you may still be able to monitor them at home, but some people may require hospitalization depending on other factors and test results.

Severe Neutropenia:

If you have a "neutropenic fever" (a fever as well as an ANC count below 500), hospitalization is usually required. People with severely low ANC counts often do not show any signs of infection when it is present. This is due to the lack of neutrophils to elicit a biological response.

Treating NeutropeniakIf your ANC reveals a low neutrophil count, treatment may be necessary to prevent infection. Mild cases of neutropenia may only require monitoring at home for signs of infection while more severe cases may need hospitalization.
In some cases, your doctor may recommend a course of antibiotics to prevent infection before it develops. This is called prophylactic antibiotic therapy.

Other medications, called growth factors or granulocyte-colony stimulating factors (G-CSF), are often used to increase white blood cell production in the bone marrow. Commonly used growth factors include:
Leukine (sargramostim)Neulasta (pegfilgrastim)Neupogen (filgrastim)

Your doctor may also want to halt or delay treatment until your neutrophil count is stable. A lowered dosage of chemotherapy may also be necessary.

Source

Neutropenia and HCV Treatment

Neutropenia - Interferon Therapy of Hepatitis C - HCV Advocate -
In conclusion, neutropenia is frequent during treatment of hepatitis C with .... The changes in neutrophil and lymphocyte counts during treatment are shown in Fig. 1. .... Among the exclusion criteria for therapy, low white blood cell and ... Bacterial infections did not occur in neutropenic patients, and the only ...

Side Effect Management: Neutropenia

Maintaining the maximum dose of interferon and ribavirin
is important for achieving a sustained virological response
(SVR) so some medical providers will prescribe an injectable
growth factor, granulocyte colony-stimulating factor (G-CSFfilgrastim),
brand name Neupogen
Hepatitis C Support Project • www.hcvadvocate.org ...

What About Neutropenia and Telaprevir ?

Excerpt From : 2008 Telaprevir, peginterferon alfa-2a, and ribavirin for 28 days in chronic hepatitis C patients

EDITORIAL

Decreases in hemoglobin, total white blood cell count, neutrophils, and platelets occurred during the study drug dosing period; median changes from baseline to day 28 were _2.8g/dL for hemoglobin (range: _6.2 to _0.8), _3.75_109/L for white blood cell count (range: _6.45 to _1.26), _2.39_109/L for absolute neutrophil count (range: _3.94 to _0.17), and _86_109/L for platelet count (range: _125 to 21). The only clinically significant hematology abnormalities were anemia in four patients and mild neutropenia in one patient.