Hep c review.pub

ANEMIA INSTITUTE FOR RESEARCH AND EDUCATION
SPECIAL EDITION MARCH 2004
LETTER FROM THE EDITOR:
There is a great deal of interest in the problems that anemia causes in the treatment of patients with chronic hepati- tis C. This problem is even more severe in patients with combined hepatitis C-HIV infection. However, although not men- tioned in any of the reviews in this edition of the Anemia Institute Review, the problem also extends to other population groups, such as patients with thalassemia, and other red blood cell diseases, patients with renal failure, and other chronic dis- eases. Anemia limits the option to treat hepatitis C, since the ribavirin will predictably exacerbate a pre-existing anemia, and may actually result in a fall in hemoglobin that is unacceptable. As a result, patients with anemia have often not been of- Anemia often complicates anti-viral therapy for hepatitis C, again more often and more severely in patients who are co-infected with HIV. Anemia may result in dose reductions of ribavirin and even in withdrawal of ribavirin com- pletely. Such modifications to anti-viral therapy may reduce the likelihood of achieving a sustained virological response. Erythropoietin may provide a means to prevent or treat some of these problems. Erythropoietin is the hormone which normally controls production of red blood cells. When the hemoglobin falls there is an outpouring of erythropoietin from the kidney, which stimulates the production of new red cells to repair the anemia. The induction of anemia during anti-viral therapy should trigger an erythropoietin response. Two studies described here describe the erythropoietin response, one study showing that the response is adequate, and the other study showing just the opposite, that the response is suboptimal. It is not clear why such disparate results were obtained. Even if the erythro- poietin response is normal, it may be that the bone marrow is unable to respond normally to the erythropoietin, because of Thus we need additional data to understand exactly how the body responds to the anemia induced by anti-viral ther- apy, so that we can tailor our treatment to reduce the impact of the anemia and provide adequate supportive therapy to
Morris Sherman MB BCh PhD FRCP(C)
Associate Professor of Medicine, University of Toronto,
Chairman, Canadian Viral Hepatitis Network, President, Canadian Association for Study of the Liver Anemia in the Treatment of Hepatitis C Virus Infection
Sulkowski MS.
RBV dose reduction or discontinuation. IFN-RBV-associated Clinical Infectious Diseases 2003; 37(Suppl 4):S315-22 anemia is more profound among co-infected patients, who have a high prevalence of pretreatment anemia and may also be tak- Hepatitis C virus (HCV) infection is a significant world- ing other medications causing anemia. Epoetin alfa admini- wide health care problem. Nearly one-third of all pa- stration to HCV-infected patients with IFN-RBV-related ane- tients infected with human immunodeficiency virus mia can significantly increase hemoglobin levels and maintain (HIV) are coinfected with HCV. Compared with HIV- significantly higher RBV doses compared with patients treated monoinfected persons, coinfected individuals experience with RBV dose reduction alone. Higher RBV doses and adher- more rapid progression of fibrosis and higher incidence of ence to HCV therapy have been associated with higher sus- cirrhosis and death as a result of liver disease. Treatment tained virologic response (SVR) rates. Maintenance of RBV for HCV infection includes ribavirin (RBV) plus inter- dose with epoetin alfa may improve adherence, thereby affect- feron alfa (IFN-α) or pegylated IFN, a combination treatment associated with anemia that may require The Anemia Institute is a non-profit organization dedicated to generating and sharing knowledge about anemia as a serious condition - particularly amongst patients and health care professionals dealing with disease and/or treatment related risk factors for anemia. Anemia Institute Review PAGE 2
Evidence that plasma concentration rather than dose per kilogram
body weight predicts ribavirin-induced anaemia
Lindahl K, Schvarcz R, Bruchfeld A, Stahle L.
solid-phase extraction in trough samples taken 4, 8 and 12 J Viral Hepat. 2004 Jan; 11(1):84-87. weeks after the treatment commenced. A total of 213 samples were obtained and the change in the haemoglobin Ribavirin in combination with interferon alpha-2 or pegy- level and the creatinine concentration was measured in lated interferon is the standard treatment for chronic hepa- addition to ribavirin. The dose of ribavirin per kg bw did titis C. The current dosage recommendations for ribavirin not correlate with the drop in haemoglobin level induced are based on body weight (bw). Ribavirin is mainly elimi- by ribavirin. The concentration of ribavirin was non- nated by the kidneys and we have recently shown that ri- linearly related to the drop in the haemoglobin level as bavirin plasma concentrations are determined primarily by revealed by fitting a standard Hill equation type dose- renal function. It is therefore reasonable to hypothesize response curve. The half maximal drop in haemoglobin that side-effects of ribavirin, i.e. anaemia, should be more was obtained at 4.4 microm. The results from this study closely related to plasma concentrations of ribavirin than suggest that the anaemia induced by ribavirin depends to the dose per kg bw. A total of 108 consecutive patients primarily on the concentration of ribavirin, and not on eligible for treatment of chronic hepatitis C were studied. the dose per kg bw. This lends further support to the idea Ribavirin concentrations in plasma were measured by high- that ribavirin should be dosed according to renal function. performance liquid chromatography (HPLC)-UV after Implications of anemia in human immunodeficiency virus, cancer,
and hepatitis C virus
Mildvan D.
mild to moderate anemia and associated QOL impairment. Clin Infect Dis. 2003; 37 Suppl 4:S293-6. Epoetin alfa effectively increases Hb and improves QOL in
Anemia is a multifactorial problem in patients with human
these patients. Many HIV-positive patients are coinfected immunodeficiency virus (HIV) infection, cancer, and hepati- with HCV. Standard HCV therapy (interferon alfa/ tis C virus (HCV) infection. New insights regarding anemia ribavirin) can cause anemia that may result in treatment symptoms and quality of life (QOL) have prompted reassess- alterations and compromised virologic outcome. Epoetin ment of traditional triggers for anemia treatment to increase alfa therapy in anemic HCV patients increases Hb levels hemoglobin (Hb) and improve QOL. In HIV-positive pa- and may provide other benefits. Neuroprotective effects of tients, anemia is independently associated with disease pro- epoetin alfa in preclinical models of central nervous system gression and survival. Many HIV-positive patients receiving disorders have recently been demonstrated, implying a new highly active antiretroviral therapy (HAART) still develop Treatment of hepatitis C and anemia in human immunodeficiency
virus-infected patients
Dieterich DT.
INFECT DIS 2002:185{SUPPL1} S128-137.
α2b/ribavirin can achieve similar response rates in HCV/HIV – co-infected individuals with no adverse effect on HIV RNA concentrations. Although adverse effects are more frequent Because of shared modes of transmission, co-infection with with combination therapy than with IFN-αmonotherapy, human immunodeficiency virus (HIV) and hepatitis C virus most are manageable. In addition, few instances of drug- (HCV) is common. Co-infection with HIV increases HCV drug antagonism have been reported among drugs used to virus load, liver-related mortality, and the risk of sexual and treat each disease, although further study is necessary. Ri- perinatal transmission of HCV and it may accelerate HCV bavirin-associated hemolytic anemia is a potential problem disease progression. With combination interferon (IFN)– in a patient population that is already susceptible to anemia α2b/ribavirin or pegylated IFN- α2b/ribavirin therapy, long- but is manageable with recombinant human erythropoietin term remission is possible for HCV-infected patients. Pre- liminary evidence suggests that the combination of IFN– Anemia Institute Review PAGE 3
Erythropoietic Response to Anemia is Decreased in Patients Infected
with Hepatitis C Virus (HCV) Receiving Combination Ribavirin and
Pegylated Interferon (RBV/PEG-IFN) Therapy
Vijayan Balan, David Schwartz, Georger Y. Wu, Andrew J. Muir, Reem
Ghhalib, John Jackson, Emmet B. Keeffe, Lorenzo Rossarom and Peter J.
Results: The analysis included 97 pts (mean age, 47.5y; 46%
men). Mean Hb decreased by 2.6 ± 1.4 g/dL from Day 1 (D1) Poster presented at 54th Annual Digestive Disease Week May 2003 to Wk 8. Mean sEPO and retics increased from D1 to Wk 8; however, regression analysis showed that the estimated Background: Studies in anemic patients (pts) with cancer
erythropoietic response (defined as the slope of the relation and HIV infection show that the inverse relationship be- between sEPO and Hb) was lower (sEPO = –18.6 Hb + 268 [r tween serum erythropoietin (sEPO) and hemoglobin (Hb) = –.56]) than in historic control pts with IDA (sEPO = -25.8 seen in control pts with iron deficiency anemia (lDA) is Hb + 316 [r =–.90], sEPO = –45.0 Hb + 518 [r = –.71]). The decreased, suggesting that pts with cancer and HIV infec- mean initial dose of RBV was 986 mg/day versus 913 mg/day tion have a blunted erythropoietic response compared at Wk 8. A total of 10.4%, 5.2%, and 1.3% of pts had 200, with controls (Spivak et al, JAMA 1989; Miller et al, 400, and 600 mg/day RBV dose reductions, respectively, from NEJM 1990). The present study was conducted to de- D1 to Wk 8. There was no change in mean PEG-IFN doses scribe the patterns of change in Hb, sEPO, and reticulo- from D1 (1.55 mcg/kg/wk) to Wk 8 (1.53 mcg/kg/wk). There cytes (retics) to evaluate if HCV-infected pts treated with RBV PEG-IFN therapy (tx) also show a diminished Conclusion: Similar to pts with cancer and HIV infection,
erythropoietic response to anemia. Historic control pts HCV-infected pts treated with RBV/PEG-IFN showed dimin- ished production of endogenous sEPO for their degree of ane- Methods: A multicenter, observational, 8-week (wk) study
mia when compared with historic control pts with lDA. These was conducted in 105 HCV-infected pts scheduled to re- data point to a multifactorial etiology for the anemia seen ceive their initial course of RBV/PEG-IFN tx. Labora- with combination HCV tx, which, as shown in preliminary tory parameters were measured weekly for 8 wks or until studies (Dieterich et al, AASLD 2002; Sulkowski et al, early withdrawal. Primary variables included changes in AASLD 2001), could be responsive to treatment with recom- How can we identify better those with recurrent hepatitis C who will
respond to therapy? What are the optimal treatment regimen and
treatment duration?
Wright TL.
regimens for patients with posttransplantation HCV disease Liver Transpl. 2003 Nov; 9(11):S109-13. are problematic since there are few prospective, randomized, 1. Treatment responses are lower in immune compro- controlled trials that evaluated different treatment regimens. mised patients such as those with hepatitis C virus (HCV) 5. If treatment is undertaken, baseline creatinine clearance disease following liver transplantation than in immune should be measured and patients should be started on a dose of ribavirin of 400mg bid, or lower if renal function is impaired. 2. Predictors of nonresponse, extrapolated from studies of 6. Tolerated peginterferon doses may be somewhat lower than immune competent patients, are overly represented in for the standard immune competent patients. It is likely that liver transplantation patients (high levels of HCV RNA lower doses will not greatly compromise response (1.0 ug/kg/ week for peginterferon alfa 2b and 135 ug/week for peginter- 3. Tolerability of peginterferon plus ribavirin therapy is lower in transplant patients than in immune competent 7. Optimal treatment duration is unknown. In patients with an patients with HCV disease, in part because of a baseline on-treatment response, at least 12 months of therapy is recom- renal insufficiency that increases the likelihood of ri- 8. More potent drugs with fewer toxicities are needed for pa- 4. Clear recommendations regarding optimal treatment tients with progressive posttransplantation liver disease. Anemia Institute Review PAGE 4
Treatment of Posttransplantation Recurrence of Hepatitis C With
Interferon and Ribavirin: Lessons on Tolerability and Efficacy
Kozhikode V. Narayanan Menon, John J. Poteruchs, Omer M. El-Amin,
more of therapy. On an intention-to-treat basis, nine pa- Lawrence J. Burgart, Walter K. Kremers, Charles B. Rosen, Russell H. Wies-
tients (35%) showed an end-of-treatment virological re- ner, and Michael Charlton
Liver Transpl 2002;8:623-629
sponse. Six of these nine patients completed greater than 6 additional months of follow-up, and all have had sustained Recurrence of hepatitis C virus (HCV) infection after or- virological responses. A histological response (decrease in thotopic liver transplantation is a major cause of graft fail- histological activity index ≥ 2) was seen in 75% of virologi- ure. The aim of our study was to determine the safety, effi- cal responders and 67% of nonresponders. Adverse events cacy, and tolerability of combination therapy with inter- requiring dose modification or cessation of therapy occurred feron end ribavirin in the treatment of recurrent hepatitis in 66% of patients. Adjuvant therapies used to support he- after liver transplantation. Twenty-six patients (18 men) moglobin levels included erythropoietin and red blood cell with histologically established HCV recurrence after liver transfusions. There were no independent pretreatment pre- transplantation for cirrhosis secondary to chronic HCV in- dictors of a virological response, perhaps because of the fection were treated with a combination of interferon alfa-2b small sample size. Combination therapy with interferon and (3 million units three times weekly) and ribavirin (800 to ribavirin may be beneficial in patients with recurrent HCV l,000 mg/d). Dosage modifications were according to a stan- after liver transplantation. The majority of patients require dard protocol incorporating laboratory values and clinical dose modifications because of side effects. Histological re- side effects. Fifty percent of patients completed 1 year or sponse is common in virological nonresponders. Normal erythropoietin response in chronic hepatitis C patients with
ribavirin-induced anaemia
Emanuele Durante Mangoni, Aldo Marrone, Donatella Saviono, Carmen Del
positive and in otherwise healthy anaemic patients, and Vecchio, Riccardo Utili, and Giuseppe Ruggiero
estimate the endogenous excess erythropoietin production Antivir Ther. 2003 Feb; 8(1):57-63. in response to ribavirin induced anaemia. Background: Ribavirin administration for chronic hepatitis
Results: Erythropoietin concentration increased signifi-
C is associated with the development of haemolytic anaemia, cantly in response to anaemia caused by ribavirin. The which affects treatment efficacy and tolerability. In a pilot physiological erythropoietin response to the ribavirin in- study, the exogenous administration of erythropoietin has duced anaemia was as adequate in HCV-positive subjects been shown to be beneficial, reducing the rate of ribavirin as it is in anaemic subjects without liver disease. The rec- dose reduction. How ribavirin administration affects normal ommended exogenous erythropoietin dose appears three- erythropoietin production has not been determined. times greater than the endogenous erythropoietin boost. Aim: To investigate the endogenous erythropoietin response
Conclusion: Chronic liver damage by HCV does not affect
in hepatitis C patients with ribavirin-induced anaemia. the physiological erythropoietin response to ribavirin in- Methods: Serum erythropoietin was measured before and
duced anaemia. While the rationale for erythropoietin during interferon-ribavirin treatment in 18 HCV- positive treatment of ribavirin-induced anaemia is not straightfor- subjects. Mathematical analysis and modelling were applied ward, the currently recommended dosing regimen should to compare the degree of erythropoietin increase in HCV- Folic acid supplementation does not prevent ribavirin-induced anemia
Gonzalez H, Rios ME, Torres EA, Munoz H, Arroyo J, Castro FJ.
P R Health Sci J. 2003 Dec; 22(4):359-62.
C. Twenty one patients enrolled in treatment protocols for hepatitis C received folic acid 1 mg daily and 22 did not. Treatment of chronic hepatitis C consists of interferon plus Groups were similar in age, gender, ribavirin dose and base- ribavirin. The major adverse effect of ribavirin is hemolytic line hemoglobin. Folic acid supplementation had no effect in anemia, a complication that limits therapy. Folic acid supple- the decrease in hemoglobin or the measured parameters of mentation is used to improve erythropoiesis in chronic hemo- hemolysis. No difference between males and females was lytic anemia. The aim of this study was to evaluate the effec- noted for hemoglobin decrease or lowest hemoglobin levels. tiveness of folic acid supplementation in the prevention of ri- In our study, folic acid showed no beneficial effect in the pre- bavirin-induced anemia in patients being treated for hepatitis

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