Answer by : Robert J. Frascino, M.D.

Ribavirin Induced Anemia
 

Approximately 10% of patients receiving ribavirin develop significant anemia (1). This anemia results mostly from intravascular hemolysis (premature break up of red blood cells within the blood vessels). The anemia is dose dependent and is not worsened by the presence of interferon therapy. It also resolves within a few weeks after discontinuation of the medicine. On the average, the hemoglobin concentration drops by 2 to 3 g/dl for patients on standard dose ribavirin (1000 mg to 1200 mg a day).

Blood Cell Deficiencies and HCV

Please visit http://www.hcvadvocate.org/index.cfm for more information.

Various blood cell deficiencies are common in people with chronic hepatitis C. HCV itself may lead certain deficiencies, although the exact mechanisms are not clear.

For example, possible hypotheses put forth to explain thrombocytopenia in people with HCV include autoimmune reactions mediated by the hepatitis C virus, decreased TPO production when the liver is damaged, and spleen enlargement related to portal hypertension. A type of severe aplastic anemia is sometimes seen in people with acute hepatitis, but it appears to be associated with an agent other than the hepatitis A, B, or C viruses. The drugs most often used to treat chronic HCV are known to cause blood cell deficiencies. Alpha interferon (both standard interferon [Intron-A] and pegylated interferon [Peg-Intron]) is associated with neutropenia and thrombocytopenia. Because different types of blood cells are affected, it is believed that interferon suppresses the bone marrow. For most people, these are not major, treatment-limiting side effects.

In contrast, hemolytic anemia (blood cell destruction) is the most common side effect of ribavirin (Rebetol), and in some cases can be severe. Combination therapy with alpha interferon and ribavirin is most likely to cause blood cell deficiencies in the first several weeks of treatment. Studies suggest that EPO can improve anemia in people taking alpha interferon/ribavirin for HCV, allowing them to tolerate higher doses of ribavirin. In severe cases, it may be necessary to reduce the dose of ribavirin or stop it altogether. Always consult your doctor before adjusting doses or stopping any drug. Finally, people with chronic HCV - especially those receiving treatment — should get regular blood tests, so that blood cell deficiencies can be detected and treated early.

_{Liz Highleyman (liz@black-rose.com) is a freelance medical writer and editor. She has a certificate in public health from the Harvard School of Public Health. She has worked as an editor of the Bulletin of Experimental Treatments for AIDS (BETA), published by the San Francisco AIDS Foundation, and as health editor for the Internet search engine Ask Jeeves}

* Additional News Articles on Anemia
 

Combination Therapy with Viramidine and Peginterferon Alfa-2a (Pegasys) Reduces Potential for Ribavirin-related Anemia
 

Viramidine, an experimental pro-drug of ribavirin, has been shown in pre-clinical studies to target liver cells, rather than red blood cells (RBC), suggesting it may have less hematologic toxicity than ribavirin.

An ongoing dose-ranging study in treatment-naive hepatitis C patients compared viramidine and ribavirin used in combination with peginterferon alfa-2a (Pegasys) to evaluate the effect of treatment on hemoglobin levels as well as anti-viral activity.

180 patients were randomized in a 1:1 ratio to receive interferon alfa-2a 180 μg/wk SQ in combination with viramidine 400 (N=47), 600 (N=43), or 800 (N=45) mg BID or ribavirin 1000/1200 mg daily (N=45).

A 24-week interim analysis assessed changes in HCV RNA and the occurrence of potential hemolytic anemia (hemoglobin <10 g/dL or ³2.5 g/dL decrease from baseline).

Results

A smaller proportion of patients who received viramidine 800-1200 mg/day had hemoglobin levels <10 g/dL or ³2.5 g/dL drop from baseline during the 24-week treatment period when compared with patients who received ribavirin (48% versus 82%).

There were notable differences in the proportion of male patients with hemoglobin <10 g/dL when compared with female patients in the ribavirin group: 19% compared to 38%.

Among patients who received viramidine 800-1200 mg/day, there were no instances of hemoglobin < 10 g/dL in both male and female patients. Differences between genders were not observed in the occurrence of a ³2.5 g/dL decrease in hemoglobin.

Other adverse events were similar among treatment groups, as were reductions in HCV RNA.

Conclusions

·   Hemolytic anemia occurs less often during hepatitis C combination therapy that includes viramidine when compared to therapy with ribavirin.

·   There appears to be gender-based differences in the occurrence of hemolytic anemia among those treated with ribavirin.

05/26/04

Reference
R Gish and others. Hepatitis C Combination Therapy with Viramidine and Peginterferon Alfa-2a Reduces Potential for Ribavirin-Related Hemolytic Anemia. Abstract 406 (plenary). Digestive Disease Week. May 15-20, 2004. New Orleans, LA.

* Additional News Articles on Anemia
 

Anemia When Taking Interferon + Ribavirin and EPO Therapy for Anemia

http://www.natap.org/2001/ddw/ddw_4.htm

This study suggests that EPO may be helpful in preventing anemia for patients receiving HCV therapy (IFN/RBV). Preventing anemia ought to improve a patient’s ability to tolerate therapy, to adhere to therapy and to remain on therapy. Interferon+ribavirin can result in significantly reduced hemoglobin (anemia) in the first few weeks of therapy. Doug Dieterich (Cabrini Hospital, NYC & NYU) reported data from a study showing that Epoetin alfa (EPO) once weekly increased hemoglobin levels significantly after they had fallen on HCV therapy(abstract 340). Also, patients were able to maintain taking a higher dose of ribavirin (lower hemoglobin can lead to reducing RBV dose), which should translate to a better virologic response. And the data suggested patients benefiting from EPO had less depression (which is a side effect of interferon and ribavirin therapy) and patients reported a better quality of life. This suggests that depression experienced on RBV/IFN may be due to at least in part to fatigue and anemia. Another study reviewed below shows less anemia was experienced by patients taking Pegasys alone (without ribavirin) compared to patients taking standard interferon with ribavirin.

As background information, Dieterich reported a major toxicity of ribavirin (RBV) is reversible hemolytic anemia. Often hemoglobin (Hb) decreases within the first 4 weeks of treatment with IFN+RBV. Hb level decreases of 3 or more g/dL occur in 60% of men and 44% of women receiving RBV/IFN alfa-2b. Ordinarily, this is managed by RBV dose reduction or discontinuation. RBV dose reduction may decrease sustained virologic response to therapy.

Although I don’t think there have been studies of this, it appears as if EPO is also being used before HCV therapy in the hopes of preventing decline in Hb or a RBV dose reduction.

At DDW, Mark Sulkowski reported (abstract 2896) women are 4.4 times more likely than men (20% vs 4.5%) to experience a Hb <10 g/dL. Men were at a greater risk (40%) than women to experience a decrease in Hb of 3 or more g/dL from baseline. Sulkowski also reported that daily IFN therapy was not associated with a greater decline in Hb than IFN three times per week by week 4 of treatment. In a subset of anemic patients with a mean Hb of 10.7 g/dL who had RBV dose reduced to 600 mg daily, Hb levels increased by a mean 1.1 g/dL at 4-8 weeks after the dose decrease. Sulkowski retrospectively analyzed treatment-related changes in Hb in about 600 participants in 2 studies (IFN naïve and experienced) randomized to receive RBV 1000 mg daily or 1000-1200 mg daily (based on weight) plus IFNa 3 MIU daily or three times per week for 48 weeks, or IFN 3 MIU daily or 3 times per week for 4 weeks followed by 3 times per week dosing. More than 80% of women at baseline had Hb 13 g/dL or greater, and more than 90% of men had 14 or more g/dl Hb. As expected, 10.3% (57/551) of patients had a Hb <10 g/dL. Hb decreased 3 or more g/dL in 54% of all patients. About 27% of men & women reached a nadir (lowest point) of 11-11.9 Hb, while many more men were able to maintain Hb 12-12.9 (25% vs 17%) and 13 or more (30% vs 10%). Sulkowski also reported that in a univariate analysis, increased age, higher baseling Hb and platelet counts, and CrCl (decreases in creatinine clearance) were significantly (P<0.5) associated with the largest Hb decreases.

Getting back to the Dieterich study. The study was an open-label, randomized, parallel-group study involving 7 centers nationwide. Patients with Hb 12 or less g/dL after starting treatment with IFN/RBV were randomized to EPO or standard of care management of anemia. The primary endpoint of the study was to follow patients for 16 weeks. Patients were HCV treatment naïve or experienced. Patients were excluded for anemia due to iron, folate or B12 deficiencies, serum ferritin <50 ng/mL, uncontrolled hypertension, primary hematologic disease such as sickle cell anemia, uncontrolled seizure dosorder, known sensitivity to human serum albumin, and known sensitivity to mammalian cell derived product.

The initial dose of EPO was 40,000 Units subcutaneously once weekly. Patients with an increase in Hb of 1 or more g/dl continued EPO. Patients with less than 1 increase stopped EPO. If HB increased to >14 g/dL for women or 16 for men, EPO was withheld. When HB subsequently decreased to 13 g/dL for women or <15 g/dl for men, EPO was resumed at 30,000 Units once weekly. I think Dieterich said he titrated (incrementally increased doses) by 5,000-10,000 to a maximum of 40,000 Units once weekly.

Primary endpoints were change in Hb, secondary endpoints were change in RBV dose, and change in quality of life measured by SF-12. The ITT analysis was at week 16, including all patients receiving at least one dose of EPO. At study entry there were 36 patients (24 men, 12 women) receiving EPO and 28 standard of care (20 men, 8 women). Age was 50 in EPO arm, and 48 in SOC arm. Weight (kg) was 88 in EPO arm, and 78 in SOC. The RBV dose (mg/day) was 953 mg/day in EPO arm (200-1200) and 951 In SOC (600-1200) arm (total dose received to that point I think).

RESULTS:

The Hb values before RBV/IFN treatment was 14.5 (10.6-16.9 range) for the 36 patients receiving EPO, and 14.6 for the SOC arm, so it was about the same before treatment.

--Prior to week 16 there were 15 (42%) discontinuations in the EPO arm vs 14 (50%) in the SOC arm.

--At the start of receiving EPO the mean HB levels were 11.0 in the EPO arm vs 11.0 in the SOC arm.

--At week 16, the mean Hb was 13.9 in the EPO arm vs 11.3 in the SOC arm.

--So, the mean change in Hb was a 2.9 g/dL increase for patients receiving EPO vs a 0.3 mean increase in the SOC arm, in other words there was no change.

--By ITT (strictest) analysis 88% (30/34) in the EPO arm had 1 g/dL or more increase in Hb compared to 28% (8/28) in the SOC arm

--Using an On-Treatment Analysis, at week 16 the mean Hb g/dL was 14.2 in EPO (n=21) arm vs 11.2 in the SOC arm (n=14)

--Perhaps more important, RBV dose was higher in the EPO arm at week 16 (ITT). Patients may be helped to tolerate adequate RBV dose by taking EPO. At study entry the mean RBV dose was 956 in the EPO vs 961 in the SOC arm. At week 16 the EPO arm dose 926 mg/day vs 782 in the SOC arm. The mean change was –179 in the SOC arm vs –31 in the EPO arm (P<0.5)

--By on treatment analysis at week 16, the RBV dose was 900 (± 238) mg/day (n=20) vs 707 (± 217) mg/day

--By ITT analysis a higher percentage of patients receiving EPO (85%, 29/34) were able to take 800 mg or more RBV per day vs 61% (17/28) in the SOC arm. Only 15% receiving EPO were taking <800 mg/day vs 39% not receiving EPO (P<0.5)

--A greater percentage of patients were able to achieve a higher weight based RBV dosing (>10.6 mg/kg) in the EPO arm compared to the SOC arm, but this was not statistically significant. This 10.6 mg/kg level was suggested by Schering as the level of RBV dosing based on weight that patients should be above to achieve a maximum virologic response using PegIntron+RBV. This has been controversial as Roche suggests RBV weight based is not necessary for Pegasys+RBV, and Roche is collecting data now to report on this question

--In both the physical and mental components of the Quality of Life Test SF-12, the patients receiving EPO had better scores than those not receiving EPO

--In total, 29 patients were treated with 40,000 Units once weekly of EPO. 5 patients were dose reduced to 30,000, 20,000 or 10,000

--Safety & tolerability: Dieterich reported EPO was well tolerated, that adverse events were similar to those expected with RBV/IFN, and adverse events wee not significantly different across the study groups (including ALT &HCV-RNA). He reported more patients had headaches in the EPO arm (26% vs 11%), and nausea (23% vs 7%), and pain (20% vs 14%). Interestingly, only 17% reported depression in the EPO arm compared to 32% in the SOC arm suggesting that fatigue may be related to depression experienced on RBV/IFN.

Less Anemia with Pegasys Alone vs Standard IFN a-2b+Ribavirin

Kenneth Rothstein (albert Einstein Med Ctr, Philadelphia) reported on a safety, tolerability, efficacy, and quality of life study comparing Pegasys alone to standard IFN a-2b+ribivarin therapy. About 200 patients in each arm received either Pegasys (IFN a-2a) 180 ug once weekly or IFN a-2b 3 MIU three times per week plus RBV 1000-1200 mg/day. Preliminary virologic response at week 24 showed the same response (56% in Peg alone arm vs 57% in the IFN/RBV arm).

The incidence of adverse events were reported as less in the Pegasys arm: less rigors, nausea, insomnia, myalgia, pyrexia, depression and pruritus (itching). Of interest to this discussion on anemia, 2% were reported to experience anemia in the Pegasys arm vs 32% in the IFN/RBV arm. About 60% in the IFN/RBV arm vs 10% in the Pegasys arm had 10 or less g/dL Hb or a drop of 3 or more in Hb. 33% vs 2% (Peg vs IFN/RBV, respectively) had 10 g/dL or less Hb or a drop of 4 or more in Hb. There was also a wide disparity when looking at drops of 5 or 6 or more in Hb or 10 or less in Hb

Patients reported better physical functioning scores, mental health, and better overall health & well-being at weeks 4 and 12 using Pegasys compared to standrard IFN/RBV. Patients also reported better distress scores and positive well being scores. Patients also reported less work and activity impairment and impairment while working due to health when receiving Pegasys compared to RBV/IFN. Less patients taking Pegasys went from employed to unemployed at week 4 or 12 (7% vs 18%). Anecdotal and study reports suggest that the severity and incidence of side effects with Pegasys+ribavirin is less compared to standard IFN a-2b 3 times per week plus RBV. Most notably less depression was reported in one study.

Internet Conference Report
 Digestive Disease Week (DDW 2004)
  May 15 - 20, 2004, New Orleans, Louisiana

Antioxidant Treatment Does Not Substantially Counter the Fall in Hemoglobin in HCV Patients Treated with Pegylated Interferon Alfa-2b (Peg-Intron) and Ribavirin

Ribavirin is commonly used in combination with pegylated interferon alfa to treat patients with chronic hepatitis C (HCV). Ribavirin can cause hemolysis and a decrease in hemoglobin (Hb) levels is common. The mechanism of ribavirin-induced hemolysis is uncertain, but an increased susceptibility of erythrocytes (RBC) to membrane oxidative damage may play a role.

The aim of the present study was to test whether antioxidant (AO) treatment would ameliorate the fall in Hb levels in HCV patients treated with pegylated interferon alfa-2b (Peg-Intron) and ribavirin.

A randomized, prospective, open-label study was designed to study the effects of AO treatment (vitamin E, 400 IU BID; vitamin C, 500 mg BID; S-adenosyl-L-methionine, 400 mg TID) in HCV patients treated with pegylated interferon alfa-2b (Peg-Intron) 1.5 mcg/kg QW) and ribavirin (800-1400 mg QD).

Treatment-naive, non-smoking patients with chronic HCV were divided into two groups: the AO group (n=17) received AO for a total of 28 w beginning 4 w before antiviral therapy, while the control group (n=24) received antiviral therapy alone.

This report focuses on measurements made at entry (6 w prior to antiviral therapy) and at 2, 4 or 12 w of antiviral therapy. RBC levels of malondialdehyde (MDA, a lipid peroxidation product) and glutathione (GSH) were also measured.

Results

The control and AO groups were well matched with respect to age (47 ± 1 vs 49 ± 2), gender (67% vs 59% male), race (83% vs 94% Caucasian), HCV genotype (79% vs 94% type 1), and baseline Hb levels (15.2 ± 0.3 vs 15.1 ± 0.3 g/dL).

Antiviral therapy for 12 w resulted in decreases in ALT activity (-60 ± 10 U/L), platelets (-45 ± 9/mm³), white blood cells (-2.8 ± 0.4/mm³) and haptoglobin (-20 ± 10 mg/dL), and an increase in retiulocytes (+1.4 ± 0.4%): none of these effects was significantly changed by AO.

RBC levels of MDA and GSH were not significantly altered by either antiviral therapy or AO. In addition, AO did not significantly ameliorate the fall in Hb levels produced by antiviral therapy after 2, 4 or 12 w of treatment.

Use of recombinant erythropoietin was similar in both groups (17% vs 12%).

Conclusion

The authors conclude, “This regimen of AO treatment with vitamin E, vitamin C and S-adenosyl-L-methionine did not substantially ameliorate the fall in Hb levels in HCV patients during the first 12 w of therapy with pegylated interferon alfa-2b and ribavirin.”

06/07/04

Reference
B R Bacon and others. Antioxidant Treatment Does Not Substantially Ameliorate the Fall in Hemoglobin in HCV Patients Treated with Pegylated Interferon Alfa-2b and Ribavirin. Abstract 1150 (poster). Digestive Disease Week. May 15-20, 2004. New Orleans, LA.

http://www.hivandhepatitis.com/2004icr/ddw2004/docs/0607/060704_d.html

Low Platelets

Some people who have used Pegasys have developed heart problems, including low blood pressure, rapid heart beats and chest pain. Pegasys can also lower levels of white blood cells, increasing your risk of developing infections. As well, this drug can reduce levels of platelets in your blood. Because platelets are needed to help your blood clot, having less-than-normal levels of platelets increases your risk of bleeding.

What happens when Ribavirin or (COPEGUS) lowers your red blood count?

Low platelets are referred to as thrombocytopenia. Low red blood cells or hemoglobin is called anemia.

Will Procrit help low platelets? No, it won't , there are other medications which can increase platelets. But if you're  anemic, definitely talk to your doctor about Procrit.

Drugs to Help low platelets:

Neumega: a growth factor that stimulates the bone marrow to increase production of platelets.

thrombocytopenia from peg-intron
By Mark S. Sulkowski, M.D. (19-Jun-2002)

Hematologic

THROMBOCYTOPENIA

Thrombocytopenia (an abnormally low platelet count) may be seen in patients treated

with interferon. Thrombocytopenia potentially increases the risk of excessive bleeding.

Common consequences of thrombocytopenia include easy bruising, ecchymoses,

petechiae, hematomas, nose/gum bleeding, prolonged bleeding from venipuncture or

invasive procedures, coffee-ground emesis, hemoptysis, hematuria, vaginal/rectal

bleeding, gross blood in stools, black tarry/stools, change in vital signs, change in

neurologic status (blurred vision, headache, disorientation), occult bleeding in urine and

feces, and excessive menses. In patients with advanced liver disease, thrombocytopenia is

commonly seen as a consequence of portal hypertension and hypersplenism.

PATHOPHYSIOLOGY

Platelets are fragments of the megakaryocytes produced and released by the bone

marrow.1 In addition to interferon, other factors may affect the number and function

of circulating platelets, such as a disease process (eg, cirrhosis), chemotherapy

(eg, interferon), some other prescription medications (eg, anticoagulants), and some overthe-

counter medications (eg, aspirin). Thrombocytopenia is likely the result of a cytotoxic

action on the bone marrow itself, preventing postmitotic cells from completing their

maturation in the blood and tissue (bone marrow suppression). If a sudden significant

drop in platelet count occurs during interferon therapy, consider ruling out idiopathic

thrombocytopenic purpura.

GRADING OF THROMBOCYTOPENIA2

Normal: 150,000 to 400,000 platelets/mm3

Mild: 50,000 to 150,000 platelets/mm3

Moderate: 25,000 to 50,000 platelets/mm3

Severe: <25,000 platelets/mm3

PREVENTIVE STRATEGIES2

1. Assess for thrombocytopenia by monitoring CBC and platelet count at baseline and at

weeks 2 and 4, and then monthly in all patients receiving anti-HCV treatment. Note:

lower platelet counts will be recorded when a CBC is obtained within 24 to 72 hours

of peginterferon administration. Consider drawing the CBC 1 to 2 days before

peginterferon administration.

2. Assess previous or current medications and/or diseases (eg, idiopathic

thrombocytopenia) for potential or significant thrombocytopenia.

3. Assess for other factors that may contribute to low platelet count (ie, abnormal

hepatic/renal function, sepsis, fever, anticoagulant therapy, aspirin use).

4. Teach patient to report any evidence of spontaneous or excessive bleeding, including

petechiae, ecchymoses, hematomas, blood in body excretions, bleeding from body

orifices (especially from nose when sneezing), or changes in neurologic functioning.

Side Effects Management Handbook • IX. Hematologic • p. 6

TREATMENT STRATEGIES2

1. Dose modify/hold drug until platelet count recovery, or discontinue per package

inserts. Peginterferon alfa-2b dose reduction by half is recommended for platelet count

<80,000/mm3, and discontinuation is recommended for platelet count <50,000/mm3.

The peginterferon alfa-2a dose should be reduced to 90 µg if the platelet count is

<50,000/mm3 and should be discontinued if the platelet count is <25,000/mm3.

2. Consider platelet transfusion (rarely necessary).

Patients should be instructed to:

1. Avoid activities predisposing to trauma or injury.

2. Avoid use of aspirin or aspirin-containing products.

3. Use electric razors rather than blades.

4. Blow nose very gently.

5. Use soft toothbrushes (not electric).

6. Promptly report any difficulties with constipation; avoid straining.

7. Apply continuous pressure for 5 minutes if observable bleeding occurs (ie, knife cut).

8. Observe and immediately report to healthcare provider any bruising, skin problems,

blood in urine/stool/emesis, vaginal/rectal bleeding, blurred vision, headache, or

disorientation.

REFERENCES

1. Johnson BL, Gross J. Handbook of Oncology Nursing. Bethany, Conn: Fleschner Publishing;

1985:229-233, 250-251.

2. McNally JC, Stair JC, Somerville ET. Guidelines for Cancer Nursing Practice. New York,

NY: Grune & Stratton; 1985:147-151.

Side Effects Management Handbook • IX. Hematologic • p. 7

Below is an excerpt from : http://www.hepnet.com/hepc/news1030B00.html 

Press Release

      Schering-Plough, Roche see gains against hepatitis C

Neumega

From : http://www.neumega.com/

Neumega is a platelet growth factor that can help prevent extremely low platelet counts caused by chemotherapy. Treatment with Neumega may help cancer patients continue their treatment without interruption.

This Web site supports the mission of WYETH to continually strive to develop innovative pharmaceuticals for the treatment of cancer patients.

BOXED WARNING

NEUMEGA is indicated for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia. Efficacy was demonstrated in patients who had experienced severe thrombocytopenia following the previous chemotherapy cycle. NEUMEGA is not indicated following myeloablative chemotherapy. The safety and effectiveness of NEUMEGA have not been established in pediatric patients.

Serious adverse reactions have been associated with NEUMEGA administration, including allergic or hypersensitivity reactions and anaphylaxis. NEUMEGA is known to cause serious fluid retention that can result in peripheral edema, dyspnea, pulmonary edema, capillary leak syndrome, atrial arrhythmias (some with strokes), and exacerbation of pre-existing pleural effusions. It should be used with caution in patients with congestive heart failure (CHF), at risk of developing CHF, or with a history of heart failure. Other more common adverse events included mild to moderate fluid retention, tachycardia, conjunctival redness, and papilledema. In randomized studies, most adverse events were reversible within several days following discontinuation of NEUMEGA