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Tropical Gastroenterology 2008.29;4:187–193 Quarterly Have hematopoietic growth factors made an Review impact on the management of disease?

Pankaj Tyagi and Kaushal Madan

ABSTRACT

Department of Gastroenterology, It is clear that the major indication for the use of hematopoietic growth factors in hepatology GB Pant Hospital & Department of is to counteract the adverse effects of (neutropenia and ) and Medical Hepatology, ribavirin (hemolytic anaemia) during the treatment of infection. This is important Institute of Liver and Biliary Sciences, because the probability of SVR depends on proper adherence to therapy (at least 80% of the New Delhi requisite dose maintained for at least 80% of the requisite duration) and proper adherence can only be achieved if the are reduced to a minimum. Even though the studies Correspondence: Dr. Kaushal Madan have demonstrated beyond doubt that the use of hematopoietic growth factors does indeed Email: [email protected] reduce the incidence and severity of these adverse effects and helps the patients to complete the course of therapy, the data on improvement of SVR is still limited. There is only one study of darbepoetin and showing the beneficial effect on SVR. Even among the hematological side effects, possibly the only significant effect which limits the use of optimal HCV therapy is the hemolytic anaemia induced by ribavirin. The other two main side effects, i.e. neutropenia and thrombocytopenia are not clinically problematic. The use of such growth factors would be particularly effective if patients who have advanced liver disease or are able to receive adequate anti-viral therapy as has been demonstrated in the study of eltrombopag among HCV cirrhotics. Apart from this, other indications of G-CSF or GM-CSF use are still in the experimental stage. So, as of now, apart from erythropoietic factors, the role played by other hematopoietic growth factors in hepatology is limited. But future research, especially in the areas of immunotherapy of liver cancers and stem cell therapy for end- stage liver disease, is surely going to give these factors their due place in hepatology.

Introduction these cells can destroy and eliminate pathogenic Therepecific efficacy of haematopoitic growth factors (HGF) in microorganisms. G-CSF is a glycoprotein that plays an the management of cancer and haematological problem have immunomodulatory role by affecting an increase in the been well established. They have been predominantly used leukocyte count, and upregulating phagocyte function during in the treatment of anaemia associated with chronic renal neutropenia. G-CSF is produced primarily by monocytes/ failure and chemotherapeutic drug-induced neutropenia. macrophages, fibroblasts, and endothelial cells and acts on Recently, an orally active receptor agonist has neutrophil precursors and mature neutrophils. It has been been introduced which can improve levels in produced commercially by recombinant technology for clinical thrombocytopenic patients. There is also a growing area of use in both glycosylated and non-glycosylated forms. use of these growth factors in hepatology, which mainly involves Glycosylation stabilises the molecule by suppressing their use in the management of cytopenias induced during polymerisation and conformational change; this leads to hepatitis C therapy. In addition, even though in the experimental resistance against degradation by human proteases. But both stages, the immunomodulatory actions of some of these forms have similar biological activities. growth factors may be useful in some types of liver disease. The major action of G-CSF is to enhance the numbers and But whether they have made a positive impact on disease functions of neutrophils. G-CSF knockout mice develop chronic outcome is to be seen. In the subsequent sections we shall neutropenia with inability to control Listeria monocytogenes discuss the roles of granulocyte colony stimulating factor (G- infection and failure to mobilise neutrophils during sepsis.1 CSF), (EPO) and eltrombopag in the This property of G-CSF is utilised in the treatment of management of liver diseases. neutropenia due to drug-induced bone marrow suppression. G-CSF has also demonstrated the ability to mobilise CD34+ Granulocyte-colony stimulating factor (G-CSF) hematopoietic stem cells from the bone marrow.2 How this is used for the management of liver disease is discussed later. The body’s major defense mechanisms against infectious G-CSF is considered a safe formulation and except for a agents include polymorphonuclear leucocytes, macrophages, 20%-30% incidence of musculoskeletal pain, it rarely natural killer cells, and cytotoxic lymphocytes. Upon activation, produces life-threatening complications. © Tropical Gastroenterology 2008 188 Tropical Gastroenterology 2008.29;4:187–193

Thrombopoietic growth factors Despite a decline in the incidence of acute HCV infection in recent years, the prevalence of HCV-related chronic liver Recombinant human interleukin 11 is a thrombopoietic growth disease is increasing in those who had acquired the infection factor that stimulates proliferation and maturation of before the introduction of the practice of screening of donor resulting in increased platelet counts. It has blood and blood products for HCV. Up to 80% of adults with been used for the treatment of severe thrombocytopenia among HCV infection develop chronic viremia. However, only a quarter patients receiving chemotherapy. It has also been used to of chronically infected patients develop chronic hepatitis, a treat HCV-related idiopathic thrombocytopenic purpura. In quarter of whom progress to cirrhosis. The disease in 1–4% doses used by Fontana et al3 in their study it also reduced the of those who develop cirrhosis leads to liver cancer annually.7 HCV RNA levels. But the major drawback of interleukin 11 is In India the prevalence of anti-HCV in the general population the high cost and its propensity to cause fluid retention, which is about 0.87% of which about 81% are viremic.8 Based on may lead to pedal oedema, pulmonary oedema and the these figures, more than 10 million Indians are estimated to capillary leak syndrome. be anti-HCV positive and >5-7 million are expected to be Thromobopoietin-receptor agonist (Eltrombopag) viremic. This is going to result in a large burden of HCV-related (GlaxoSmithKline) is a new, small-molecule, non-peptide, oral complications of cirrhosis and liver cancer in the coming years. platelet growth factor. This drug interacts with the India is moderately endemic for the hepatitis B virus (HBV), and induces proliferation and with nearly 4% of its population, i.e. about 40 million people differentiation of megakaryocytes and results in an increase acting as chronic hepatitis B virus (HBV) carriers, most of who in platelet production. Eltrombopag therapy has been shown are asymptomatic (high endemicity >8%, intermediate 2%– to stimulate proliferation and differentiation and 8%, low <2%). Carriers of HBV are at increased risk of to cause a dose-dependent increase in platelet counts in both developing cirrhosis, hepatic decompensation, and animal and human studies.4 ,5 hepatocellular carcinoma (HCC). Although most carriers will not develop hepatic complications from chronic hepatitis B, Erythropoietin 15% to 40% will develop serious complications during their lifetime. HBV is the major cause of chronic hepatitis, cirrhosis Erythropoietin is a glycoprotein produced primarily in the and primary liver cell cancer in India. About 50% of chronic kidneys that stimulates the division and differentiation of liver disease in India is due to HBV infection and 20% due to committed erythroid progenitors in the bone marrow. HCV infection.9 Recombinant human erythropoietin was first licensed as EPOGEN in 1989 for use in patients on renal dialysis, and it HCV therapy: importance of adherence and eliminated the need for repeated transfusions in this complications of treatment population. Recombinant erythropoietin is available commercially as Epogen, Eprex, and Procrit and as a Despite many advances in research on HCV therapy, hyperglycosylated longer-acting form, . These interferons and ribavirin are the mainstay of HCV treatment. drugs have been licensed for the treatment of anaemia Rapid improvement in the treatment of HCV infection during associated with chronic renal failure, chemotherapy for non- last decade includes, optimisation of duration of myeloid cancers, zidovudine treatment of HIV, and to reduce according to prevalent genotype, increase in ribavirin dose the use of allogeneic blood transfusions in surgery patients. and avaialbility of pegylated interferon. The protease inhibitors Epogen is indicated for the treatment of anaemia in dialysis in the management of HCV infection are currently being patients with chronic renal failure. evaluated. These therapies are associated with several Plasma erythropoietin levels remain relatively constant hematopoietic side-effects such as anaemia, when haemoglobin levels remain at or above 12 g/dL but thrombocytopenia and neutropenia, causing interruptions in begin to rise rapidly and markedly when the haemoglobin therapeutic schedule. Such interruptions or dose reductions level falls below 12 g/dL. It takes 3 to 4 days following are known to result in sub-optimal therapeutic efficacy. erythropoietin stimulation for circulating reticulocytes to There is no effective vaccination for HCV. The only option increase. Depending on the degree of anaemia, maturation available for reducing the risk of cirrhosis and liver cancer in of circulating reticulocytes into mature red blood cells (RBCs) HCV infected patient is anti HCV treatment, is by means of may take an additional 1 to 3 days. Thus, any clinically effective anti-viral therapy. The best parameter for assessing significant increase in the haemoglobin levels is usually not response to therapy is the sustained virological response observed in less than 2 weeks following erythropoietin (SVR) and it has been demonstrated that patients with chronic stimulation and may require up to 6 weeks in some patients. hepatitis C who are able to achieve SVR have lower risk of One significant adverse event reported with long- term use progression to cirrhosis.10 Patients who achieve SVR have a of erythropoietin in patients with chronic renal failure, is the lower incidence of HCC as compared with those without SVR development of pure red cell aplasia secondary to the or those who were untreated.11 In a study of 738 patients with development of anti-erythropoietin antibodies.6 This may not chronic hepatitis C infection (594 received treatment and 144 be apparent on short-term use. did not), the hazard ratios for the development of HCC were 0.16 (0.04-0.62), 0.27 (0.09-0.79) and 0.74 (0.37-1.48) among The burden of viral infection related chronic liver sustained responders, transient responders and non- disease responders respectively, signifying the importance of achieving SVR.12 Chronic HCV infection affects approximately 300 million Adherence to therapy is an important factor to achieve SVR. people worldwide and is a major cause of cirrhosis, end- In a retrospective study comprising pooled data (1521 patients stage liver disease, and hepatocellular carcinoma (HCC). receiving either standard or pegylated interferon based Hematopoietic growth factors in liver disease management 189

regimens), it was demonstrated that patients receiving < 80% mechanisms to hydrolyse ribavirin, it keeps getting of one or both for < 80% of the duration of therapy accumulated. During combination antiviral therapy, had suboptimal SVR rates compared with patients who haemoglobin usually decreases by 2.5–3.0 g/dL, within the received > 80% of the assigned duration of therapy. Adherence first 4 weeks of treatment. Such decrease in haemoglobin is to therapy (>80%) increased the SVR rate from 52% to 63% in mantained through the treatment duration despite reduction patients who received pegylated interferon á 2b (PEG-IFN á2b) in the dose of ribavirine. About 20% of patient recieving and Ribavirin (RBV) (p=0.04). In the groups receiving standard combination of interferon and ribavirin needs reduction in 18,19 interferon the difference did not reach statistical significance ribavirin dose for decrease in haemoglobin. More than half and in the groups receiving weight- based ribavirin and of patients treated with interferon and ribavirin have been 19 pegylated interferon, the difference was significant only in reported to have a haemoglobin decrease of 3 g/dL. Anaemia genotype 1 patients.13 In this particular study the authors were contributes to treatment-related fatigue, shortness of breath, not able to dissect the importance of adherence to interferons and other symptoms that impair the quality of life (QOL) further or ribavirin. Even the advantage of achieving an early virological contributing to dose reduction/interruption of therapy in up to a response (EVR, defined as a 2 log reduction in viral load at 12 third of patients. weeks of therapy) is lost if adherence to therapy is not The incidence of anaemia is significantly higher in certain maintained for the remaining duration of treatmnet.14 subgroups of patients, such as HIV/HCV co-infected patients The dose of ribavirin has been identified as an important and patients who have recurrent HCV after liver transplantation. variable for relapse. Patients who receive ribavirin in doses >10.6 mg/kg have higher SVR than those who receive <10.6mg/kg dose.15 In a prospective randomised trial in 1311 HCV infected patients, it was demonstrated that the SVR was Erythropoietin for treatment of anaemia during HCV 63% and 52%, respectively in the groups receiving 1000-1200 therapy (Table 1) mg/day and 800 mg/day doses of ribavirin along with pegylated interferon alpha 2a for 48 weeks.16 This difference was Before the advent of erythropoietin physicians managed apparent mainly in patients infected with genotype 1 HCV. anaemia related to treatment of hepatitis C with reduction in Higher concentrations of ribavirin in whole blood after 4 weeks ribavirin dose. The product information for peginterferon/ of treatment have also been associated with a higher ribavirin recommends ribavirin dose reduction by 200 mg/day response rate, and the probability of response increased with (for peginterferon á-2b/ribavirin) or to 600 mg/day (for increasing concentration.17 Thus, it is apparent that in order to peginterferon á-2a/ribavirin) if the haemoglobin decreases to achieve an appreciable SVR, we need to maintain higher drug <10 g/dL in a patient without cardiac risk factors, and doses for at least 80% of the required duration of therapy. discontinuation of ribavirin if haemoglobin becomes <8.5 g/ Because of a number of side-effects associated with the use dL. Dose reduction generally stabilises the haemoglobin level of interferons and ribavirin, this goal can only be met if the but, on an average, produces an increase of only 1 g/dL. associated side effects are aggressively managed or are not Because of its effect on erythrocyte precursors, allowed to occur at all (if possible). The most important dose erythropoietin has been used to treat ribavirin-induced limiting side-effect associated with the use of interferons and anaemia during the treatment of HCV. Dieterich and colleagues ribavirin is hemolytic anaemia due to ribavirin, and bone marrow in an open label study randomised 36 patients to receive suppression, neutropenia and thrombocytopenia due to epoietin alfa ( 40,000 U/week) and 29 to receive placebo. Mean interferons. change from baseline haemoglobin level at week 16 was +2.8 Most of the available data on the importance of adherence g/dL for the epoietin alfa group and +0.4 g/dL in the placebo to interferon therapy has been evaluated for hepatitis C group; the difference was statistically significant (p<0.0001). treatment. Howevere, similar informations is not available for The ribavirin dose reduction required was also significantly hepatitis B, but the importance of adequate treatment duration lower in the epoietin group (-34 mg/d vs. –146 mg/d; p=0.06)). and dose of interferon should not be ignored in patients with In addition to a significantly higher haemoglobin level at week hepatitis B as well. 16 (13.8 vs. 11.4; p<0.0001), HRQOL was also significantly better in patients receiving epoietin alfa at week 16.20 In another Clinical use of hematopoietic growth factors double-blind study, 186 patients were randomised to receive Anaemia epoietin alfa (n = 95) 40,000 U/week by subcutaneous injection for 16 weeks or placebo (n = 91) for 8 weeks. Epoietin alfa In hepatitis C patients, the National Anemia Action Council maintained the RBV dose in 88% of patients as compared specifies the laboratory definition of anaemia as haemoglobin with only 60% of patients on placebo. Patients on epoietin alfa <11 g/dL or hematocrit <33%. Anaemia contributes to in the double-blind part of the study demonstrated a mean treatment-related fatigue, shortness of breath, and other increase in haemoglobin of 1 g/dL by week 4, with a further symptoms that impair the quality of life (QOL). increase to 2.2 g/dL at the end of the study period. In the open- Anaemia occurring during HCV therapy is multifactorial, label part of the study, patients on placebo crossing over to which includes ribavirin induced hemolysis, interferon-induced epoietin alfa achieved a mean increase in haemoglobin of 2.0 bone marrow suppression and ribavirin induced down- g/dL, and mean haemoglobin at the end of the open-label regulation of erythropoietin receptors.18 Ribavirin is study was no different from that of patients maintained on concentrated in the red blood cells (RBCs) and ribavirin epoietin alfa throughout the study.21 Adverse events in this concentration in RBC is 60 times higher than that in the serum. study were similar in both groups of patients except for nausea, Ribavirin is converted to ribavirin triphosphate in the RBC, which was more common in the epoietin alfa treated group. leading to depletion of ATP within the RBCs causing oxidative Six serious adverse events occurred during the study; five membrane damage and hemolysis. Since RBCs lack occurred in the epoietin group. 190 Tropical Gastroenterology 2008.29;4:187–193

Although erythropoietin does reduce the incidence of alpha (3 mg/kg once every 2 weeks), if the haemoglobin was anaemia and helps maintain adherence to anti-HCV therapy, <10.5g/dL, and G-CSF if they had neutropenia. After 81 days, its impact on the treatment of HCV will be demonstrated only darbepoetin alpha produced an increase in the haemoglobin if its use leads to an increase in the SVR. In a recent study of level by 1.9 + 1.0 g/dL%.22 Treatment with growth factors was darbepoetin alpha (another erythropoiesis stimulating growth an independent predictor for SVR. This is probably the only factor) and G-CSF for the management of anaemia and demonstration of an improvement in SVR with the use of neutropenia during hepatitis C virus treatment, 101 patients erythropoeitic growth factors. were analysed. In addition to pegylated interferon alpha-2b and weight-based ribavirin dosing, they received darbepoetin

Table 1: Summary of studies showing the effect of erythropoietin

Number of patients Indication for Therapy given Change in Hb % of patients and type of study starting to maintain treatment RBV=800mg/day Talal et al, 200140 18 patients open Hb<10 g/dL; Epoetin alpha 40,000 10.6±1.0 to 12.7±1.3 label pilot study fall of Hb>2 g/dL IU/ week sc on therapy Gergely et al, 200241 13 patients, non- - 4000-10000 IU three 10.2 to 11.5 randomised study times a week Dietrich et al, 200319 64 patients, prospectively Hb<12 g/dL Epoetin alpha 40,000 IU/ Increase of Hb of 83% randomised study week sc for 16 wks 2.8 g/dL from the base line in treatment group Afdhal et al, 200420 185 patients, prospectively Hb<12 g/dL Epoetin alpha 40,000 IU/ Increase of Hb of 80% randomised study week sc for 26 weeks 2.2±1.3 g/dL Younossi et al, 200721 101 patients, prospectively Hb<10.5 g/dL Darbepoetin alpha 3 ì g/kg Increase of Hb of 78% randomised study once every 2 weeks 1.9±1.0 g/dL Hb: Haemoglobin; sc: subcutaneous; RBV: Ribavirin

Neutropenia during HCV treatment

Neutropenia during HCV therapy occurs due to direct bone independent factors for prescribing G-CSF for HCV treatment marrow suppression caused by interferon therapy. The were younger age of the physician (<45 years), practice in a absolute neutrophil counts decrease by 30-50% from the university hospital and high load of HCV patients.24 baseline value during HCV therapy with interferons.23 The The issue of G-CSF making an impact on HCV therapy neutorophil counts usually drop in the first 2 weeks of therapy has two aspects. First, has the use of G-CSF resulted in and then stabilise during the remainder of treatment. During significant improvements in the SVR? Again, there is only one 22 trials using pegylated interferons, it was observed that study which has tried to answer this. In this study, both neutropenia was the most common cause of dose reduction darbepoetin and G-CSF were used as hematopoietic growth (being present in 18% of dose reduction cases) but rarely factors along with pegylated interferon alpha 2b and weight- was responsible for discontinuation of therapy (<1% of based ribavirin therapy. Patients who developed neutropenia discontinuation cases). (absolute neutrophil counts <750/mm3 ) received G-CSF in a The fear of infectious complications with interferon induced dose of 150 ì gm/ every week to 300 ì gm thrice a week. Low neutropenia has led to recommendations (by the viral load, non-genotype 1 infection and treatment with manufacturers of interferons) that pegylated interferon dose hematopoietic growth factors were independently associated should be reduced by 25-50 % if the neutrophil count goes with SVR. below 750/mm3 and the drug should be discontinued if the Second, do we really need to use G-CSF for low neutrophil neutrophil count goes below 500/mm3. However such an counts when studies have not been able to demonstrate any increase in infectious complications with interferon therapy increase in infectious complications secondary to interferon has not been demonstrated in clinical studies (discussed induced fall in white blood cell counts? There are no reports to later). implicate neutropenia as a risk factor for infections during anti-HCV therapy. In a retrospective study comprising, 192 G-CSF for treatment of neutropenia during HCV chronic hepatitis C patients, 67 infectious complications therapy occurred in 57 patients, but the infectious complications were neither correlated with the nadir of the neutrophil counts nor Although there are no guidelines for the administration of G- with the the degree of fall in neutrophil counts from baseline.25 CSF in the treatment of neutropenia during HCV therapy, many In another study of 119 patients who received standard hepatologists use this growth factor whenever there is a fall in interferon and ribavirin therapy, the neutrophil count decreased neutrophil count during interferon use. In a recent survey con- to <750/mm3 in 9% and to <500/mm3 in 2%. it was ducted in France on the practice of physicians prescribing demonstrated that 9% developed neutrophil counts <750/mm3 growth factors during HCV therapy, it was shown that G-CSF and 2% developed neutrophil counts <500/mm3. Even though was prescribed in a dose of 300 ìg, 1-3 times a week. The 18% patients developed infectious complications, a main indication was a neutrophil count of 400-750/mm3. The comparison of patients with and without infection revealed no Hematopoietic growth factors in liver disease management 191 difference in either baseline neutrophil counts nor in the degree Availability of an orally active drug for management of of fall in neutrophil counts during therapy.26 Therefore, evidence thoromobocytopenia, makes management very easy, in favour of association between neutropenia during HCV especially because it avoids the dangers and inconvenience treatment and infection is not available. Further, randomised of repeated platelet transfusions. In patients of HCV-related trials need to be carried out evaluating the need and impact of cirrhosis undergoing antiviral therapy, ongoing administration G-CSF as an adjuvant / add-on with interferon-based regimens of eltrombopag at 75 mg daily enabled significantly more for HCV. patients to both commence combination antiviral therapy with Having said that, it is also true that whenever interferon pegylated IFN and ribavirin and then to successfully complete based treatment is given to patients who are cirrhotic27,28 or 12 weeks of treatment compared with placebo (65% vs. 6%). who have HIV co-infection or in post-liver transplantation cases, Importantly, despite eltrombopag therapy, platelet counts the incidence of infectious complications increases. In such decreased in all eltrombopag treatment groups while patients situations the use of G-CSF may be justified in order to maintain received antiviral therapy, but continued to remain over 50,000/ adequate neutrophil counts. But again systematic studies mL3. Insignificant side effects such as headache, dry mouth, need to be carried out even in such situations. abdominal pain and nausea have been reported with the use of eltrombopag.31 But it is yet to be seen whether this completion Thrombocytopenia during HCV therapy of therapy with concomitant use of eltrombopag will translate to improvement in the SVR in patients of HCV undergoing Thrombocytopenia is a common manifestation of chronic liver therapy with interferon and ribavirin. If the patients who have disease, and its prevalence correlates with the severity of advanced fibrosis or cirrhosis receive adequate therapy, and hepatic injury. In chronic liver disease, it is usually a are able to eradicate the virus from their bodies, they will have manifestation of portal hypertension and hypersplenism. In a lower risk of developing complications, and this group will addition hepatitis C may cause thrombocytopenia by auto- then constitute the best target for the use of such growth factors. immune mechanisms. Patients receiving interferon or This is the only way eltrombopag will have an impact on HCV pegylated interferon in chronic hepatitis experience a fall in treatment. platelet count, due to bone marrow suppression, but platelet counts < 75,000/mm3 are rare and seldom require dose Other indications of hematopoietic growth factors in reduction or discontinuation. Peck-Radosavljevic et al,29 hepatology showed in their study of cirrhotic and non-cirrhotic HCV patients on standard IFN, that platelet counts decreased by G-CSF for mobilisation of bone marrow stem cells 32% and 35%, respectively. They also demonstrated a blunted G-CSF also promotes the proliferation and mobilisation of thrombopoietin response to falling platelet levels among bone marrow progenitor cells [peripheral blood stem cells patients with advanced liver disease (cirrhotics vs. non- (PBSC)], which may be pluripotent and may differentiate in to cirrhotics), suggesting that recombinant human cells of hepatic lineage helping in liver regeneration. Four to thrombopoietin may be of value in patients developing six days after administration of G-CSF CD34+ PBCs begin to thrombocytopenia during interferon therapy. rise in the peripheral blood.32 The optimal dose of G-CSF for The manufacturers of pegylated interferon suggest that this purpose is about 10-16 ì g/kg/day leading to a harvest of the dose of PEGIFNa-2a should be reduced by 50% in patients about 4.9 x 106/kg to 7.1 x 106/kg PBSCs on day 5.33 who develop a platelet count of <50,000/mm3, and should be In a recent study G-CSF was used to help mobilise discontinued in patients who develop a platelet count of autologous bone marrow derived stem cells (CD 34+) from <25,000/mm3. Reduction by 50% is recommended with patients with alcoholic liver disease. The cells after PEGIFNa-2b in patients who have a platelet count of <75,000/ leukapharesis and in-vitro expansion were transfused back mm3, and discontinuation is recommended in patients who in to the hepatic artery of these patients resulting in have a platelet count of <50,000/mm3. Even though improvement in bilirubin, Child’s scores and ascites.34 thrombocytopenia occurs during therapy with interferons, Although stem cell therapy for chronic liver disease is still in spontaneous bleeding episodes rarely occur in such patients. the experimental stages, the use of G-CSF is integral to this form of therapy and in the near future, if this therapy succeeds Thrombopoietic growth factors for treatment of 3 in improving the survival of patients with end-stage liver thrombocytopenia during HCV therapy disease, G-CSF will have a significant impact in the field of hepatology. Recombinant human interleukin-11 (Neumega [oprelvekin]) As mentioned earlier, one study has used interlueukin 11 to G-CSF/Granulocyte Macrophage (GM)-CSF as treat HCV-related thrombocytopenia, but no published study has looked for the effect of interleukin 11 on thrombocytopenia immunotherapeutic agents for liver tumours induced by interferon therapy. GM-CSF has the ability to induce dendritic cells, which in turn stimulate tumour specific cytotoxic T lymphocytes (CTLs) 35 Thromobopoietin-receptor agonist (Eltrombopag) leading to tumour regression. GM-CSF has been used in experimental liver tumours along with IL-12 as a form of successful cancer immunotherapy.36 But this too is In a randomised controlled trial, eltrombopag was used in experimental use of GM-CSF and a lot of research needs to doses of 30 mg, 50 mg and 75 mg among patients with done before this will make any difference in the practice of idiopathic thrombocytopenic purpura who were resistant to hepatology. Table 2 summarises the beneficial effects of standard therapy. Twenty eight percent, 70% and 81% of these hematopoieitic growth factors in liver disease. patients in the three dose groups, respectively were able to 3 achieve an increase in platelet count to over 50000/mm .30 192 Tropical Gastroenterology 2008.29;4:187–193

Table 2: Current and potential hepatic conditions where GM-CSF as an immunoadjuvant along with hepatitis B hematopoietic growth factors have a role vaccine Hematopoietic growth Clinical use Although the response rate (development of protective anti- factor HBs titres) to the recombinant hepatitis B vaccine in healthy G-CSF Interferon induced neutropenia individuals is more than 95%, lack of response is an important problem among patients with chronic renal failure on Mobilisation of CD34+ stem cells for liver regeneration hemodialysis. Ensuring seroconversion is also important in individuals who are at high risk of acquiring HBV infection, Immunotherapy for liver cancer such as healthcare professionals, laboratory workers, and Erythropoietin Ribavirin-induced hemolytic anaemia close contacts of infected patients. In such cases GM-CSF Eltrombopag Interferon-induced thrombocytopenia has been used as an adjuvant in order to increase the efficacy GSF: Granulocyte-colony stimulating factor of the recombinant hepatitis B vaccine. The first study from

Table 3 : Hematopoietic growth factors – indications during HCV therapy and doses

Type Indication Dose Erythropoietin Epoetin alpha, Hb<10 g/dL; Fall of Hb>2 g/dL; Epoetin alpha 40,000 IU/ week sc for 16 weeks; Darbepoetin alpha Symptomatic anaemia Darbepoetin alpha 3 ì g/kg once every 2 weeks for 16-24 weeks G-CSF Filgrastim, Absolute neutrophilic count <750/mm3 Filgrastim – 150 ì g once a week to 300 ì g thrice a week Thrombopoietin- Eltrombopag Platelet counts< 70000/mm3 50-75 mg/day receptor agonist GSF: Granulocyte-colony stimulating factor; Hb: Haemoglobin; s.c.: subcutaneous

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