Considerations in the management of hepatitis C virus-related thrombocytopenia with eltrombopag.

Thrombocytopenia is a common clinical problem in HCV-infected cases. Multiple studies have consistently shown a rise in platelet count following a successful HCV treatment thus proving a cause-effect relationship between the two. Although, many therapeutic strategies have been tried in the past to treat HCV-related thrombocytopenia (e.g. interferon dose reductions, oral steroids, intravenous immunoglobulins, splenectomy etc), the success rates have been variable and not always reproducible. After the cessation of clinical trials of PEG-rHuMGDF due to immunogenecity issues, the introduction of non-immunogenic second-generation thrombopoietin-mimetics (eltrombopag and Romiplostim) has opened up a novel way to treat HCV-related thrombocytopenia. Although the data is still sparse, eltrombopag therapy has shown to successfully achieve the primary endpoint platelet counts of >/=50,000/muL in phase II& III, randomized, double-blind, placebo-controlled trials. Likewise, though it is premature to claim safety of this drug especially in high-risk patient groups, reported side effects in the published literature were of insufficient severity to require discontinuation of the drug. Based on the current and emerging evidence, a review of the pharmacologic basis, pharmacokinetics, therapeutic efficacy, safety profile and future considerations of eltrombopag in the context of HCV-related thrombocytopenia is given in this article. A MEDLINE search was conducted (1990 to August 2009) using the search terms eltrombopag, HCV, thrombocytopenia.

Hepatitis C virus (HCV) infection, even in the absence of overt hepatic disease, is a well-established cause of chronic immune thrombocytopenic purpura (CITP).[12] Six cross-sectional studies have reported positive HCV serology in almost 20% patients with a clinical diagnosis of CITP.[34] Pockros et al., retrospectively estimated that the prevalence of CITP among their HCV patients was much greater than would be expected by chance ( P < 0.00001). [56] The severity of thrombocytopenia can be highly variable ranging from a transient, isolated finding to a severe, life-threatening condition. Multiple treatment strategies have been employed to treat HCV-related thrombocytopenia but due to the heterogeneous nature of the disease, the response rates are variable, often disappointing and associated with high risks.[7] After the cessation of clinical trials of PEG-rHuMGDF due to immunogenecity issues, the introduction of non-immunogenic second-generation thrombopoietin (TPO) mimetics has opened up a novel way to treat thrombocytopenia. In 2008, FDA approved using eltrombopag and Romiplostim in patients with CITP who are refractory to at least one standard treatment.

DISCUSSION

Cause-effect relationship between hepatitis C virus infection and thrombocytopenia

It is suggested that all thrombocytopenia patients with risk factors for HCV (h/o multiple blood transfusions, hemodialysis, unexplained abnormal aminotransferase levels, needle stick injury or mucosal exposure to HCV-positive blood, I/V drug abusers, recipients of organ transplant, children born to HCV-infected mothers, current sexual partners of HCV-infected persons or persons having multiple sexual partners) be screened for the virus, especially in regions with high rates of infection.[89] Improvement in platelet counts that follow successful treatment of HCV clearly demonstrate the cause-effect relationship between the two.[1011] HCV-related thrombocytopenia (defined as a platelet count of 20,000 to < 70,000/mm3) is typically less severe than primary (idiopathic) CITP, but the affected patients are more vulnerable to major bleeding. Possible causes include decreased platelet production (due to decreased hepatic production of thrombopoietin[1213] and virus-induced bone marrow suppression),[1415] increased peripheral destruction of platelets (immune-mediated5and hypersplenism leading to increased splenic platelet sequestration),[1617] deranged clotting profile, portal hypertension (predisposing to variceal bleeding) etc. HCV binding to platelet membrane with consequent binding of anti-HCV antibody and phagocytosis of platelets, and derangement of host immune system triggering the production of autoantibodies against platelet glycoproteins are the two most frequently postulated immune mechanisms explaining increased peripheral platelet destruction in HCV-infected cases.[5141819] Interferon (IFN) therapy is also known to cause a 10-50% fall in the platelet count. It is more severe with pegylated interferon/ribavirin (PEG-IFN/RBV) combination therapy as compared to non-pegylated IFN/RBV therapy. It is worst with PEG-IFN monotherapy,[20] suggesting that some reactive thrombocytosis may be occurring secondary to RBV-induced anemia. Since successful treatment of HCV infection has clearly shown to improve the platelet counts,[521] the therapeutic protocols for managing HCV-related thrombocytopenia ought to significantly differ from those of primary (idiopathic) thrombocytopenic purpura.

Different therapeutic strategies to treat hepatitis C virus-related thrombocytopenia

Multiple therapeutic strategies including a reduction in the dose of IFN,[22] oral steroids,[4102324] intravenous immunoglobulin (IVIG)[3] or anti-RhD Ig,[9] splenectomy [410] and partial splenic embolization have been tried to treat HCV-related thrombocytopenia.[25] Unlike CITP, use of steroid therapy in the management of HCV-related thrombocytopenia has never gained popularity because despite conflicting reports of variable increases in platelet counts, steroid therapy has shown to cause a rise in transaminase levels and HCV viral load, and worsening of liver damage.[9] Steroids have even shown to cause an elevation in serum bilirubin levels and development of overt jaundice, though rarely.[9] Splenectomy has shown to produce comparable responses in HCV-positive and HCV-negative CITP cases.[410]

The most practical strategy in treating HCV-related thrombocytopenia is based on the principle that eradication of HCV infection should result in remission of thrombocytopenia. Thus the usual protocol to treat HCV-related thrombocytopenia is to continue with IFN therapy but reduce its dose if platelet count falls to < 30 × 109/L or discontinue if it falls to < 20 × 109/L. [2226] The minimum effective dose of PEG-IFN appears to be 1 µg/kg/week. If platelet counts of < 30 × 109/L persist even after reducing PEG-IFN dose to the minimum effective level, initiating some adjunct therapy like Eltrombopag may be considered.

Use of 1st-generation thrombopoietic growth factors in treating hepatitis C virus-related thrombo cytopenia-A historical note

Thrombopoietin (Tpo), a glycoprotein primarily produced in the liver, is the major regulator of both megakaryopoiesis and platelet production in human body. It is the key endogenous ligand for thrombopoietin receptor (TpoR) found on the surface of megakaryocytes, and megakaryocytic precursors.[2728] Tpo binding to its receptor activates the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathway ultimately leading to the release of platelets in the circulation.[29-31] Although, the use of first-generation thrombopoietic growth factors (recombinant human thrombopoietin [TPO] and pegylated recombinant human megakaryocyte growth and development factor [PEG-rHuMGDF]) clearly showed improvement in platelet counts in multiple clinical trials,[32-35] their use was abruptly abandoned in 1998 when some patients paradoxically developed thrombocytopenia as a result of treatment with PEG-rHuMGDF.[36-39] The underlying mechanism was development of antibodies against PEG-rHuMGDF, which cross-reacted with and neutralized endogenous TPO, producing thrombocytopenia. Some nonimmunogenic second-generation thrombopoietic growth factors have been tried since, the most extensively investigated being romiplostim [AMG-531, Nplate(R)] and eltrombopag [SB-497115, Promacta(R), Revolade(R)].[40]

Role of eltrombopag (2nd-generation thrombopoietic growth factor) in treating hepatitis C virus-related thrombocytopenia

Mechanism of action

Eltrombopag is a first-in-class, nonpeptide, orally bioavailable, thrombopoietin-receptor (TpoR) agonist, human platelets growth factor.[41-43] It interacts with the transmembrane domain of the thrombopoietin receptor, activating JAK2/STAT signaling pathways and inducing increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and thus increased platelet production.[44] It appears that eltrombopag binds the TPO receptor at a distance from the binding site for TPO and appears to initiate signal transduction by a mechanism different from rhTPO.[45] The two thus have an additive (and not competitive) effect on platelet production.

Pharmacokinetics

It appears that the pharmacokinetics of Eltrombopag (average T1/2> 12 hours) is linear and therefore it produces a dose-dependent increase in platelet proliferation and differentiation in CITP cases[4246-49] with no rebound thrombocytopenia following discontinuation of treatment. [50] In one study,[51] subjects receiving 75 mg of eltrombopag once daily started to show a rise in platelet [SUPPORTING:1] count at day 7, which peaked on day 16. Eltrombopag therapy has not been shown to produce any negative effect on platelet function, as measured by platelet aggregation and activation.[5253]

In a phase 2 study,[54] whereas only 6% of HCV-related cirrhotics in the placebo group completed the 12 weeks antiviral course, the same was completed by 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, and 75 mg of eltrombopag, respectively. Moreover, 75 to 95% of patients in the eltrombopag groups achieved the primary end point (a platelet count 100,000/mm3at week 4) in a dose-dependent manner.

Evidence of therapeutic efficacy

In a recent phase III, randomized, double-blind, placebo- controlled study,[55] CITP patients from 63 sites in 23 countries having platelet counts of < 30,000/µL received once-daily eltrombopag 50 mg (n = 76) or placebo (n = 38) for up to six weeks. The primary endpoint in this study was the determination of the proportion of patients who successfully achieve platelet counts of ≥50,000/µL at day 43. It was shown that compared to 16% placebo patients, 59% eltrombopag patients successfully achieved the primary endpoint (odds ratio [OR] 9.61 [95% CI 3.31-27.86]; P < 0.0001). Consequent to a rise in the platelet count, eltrombopag patients had less bleeding at any given time during the study than did those receiving placebo (OR 0.49 [95% CI 0.26-0.89]; P = 0.021). The effect in rise of platelet count was, however, transient with platelet counts generally falling back to the baseline levels within two weeks of halting eltrombopag therapy. The frequency of grade 3-4 adverse events leading to the discontinuation of the study were similar in both groups (eltrombopag 4% and placebo 5%).

Results from another phase II placebo controlled, double-blind, dose-ranging study,[56] done in patients with chronic hepatitis C liver disease with concomitant thrombocytopenia (platelet counts ranging from 20-70 × 109/L) showed median platelet counts in eltrombopag arm at week 4 of 53 × 109/L, 137 × 109/L, 214 × 109/L, and 209 × 109/L. This rise in platelet counts helped initiate a twelve week long interferon therapy, which was successfully completed by 6%, 36%, 53%, and 65% of the subjects, respectively.

Safety profile of eltrombopag

Although more studies are needed to ascertain the safety of eltrombopag therapy, the most commonly reported side effects in the published literature (headache, dry mouth, abdominal pain, and nausea) were of insufficient severity to require discontinuation of the drug.[53] Additionally, one study showed a significant reduction in the incidence of WHO-defined bleeding with six weeks eltrombopag therapy compared with the placebo.[57] Our knowledge whether a rise in eltrombopag-induced platelet count will increase the rate of thrombosis - vascular outcome data-is limited.[58] What we know from the data from studies of the first-generation thrombopoietic growth factors is that a rise in platelet count did not increase the rate of thrombosis, even when patients had cancer.[59-61] But notably, all those studies excluded patients with active cardiac or cerebrovascular disease or a history of thrombosis. Thus we don′t exactly know at this stage, how unsafe or risky eltrombopag administration would be in these high-risk patients. It is sound to say that worsened cardiovascular and stroke outcomes may be the major obstacle to the success of this otherwise promising agent. A recent encouraging study by Erhardt JA et al.,[62] demonstrated that in contrast to rhTPO, which significantly primed platelet activation, eltrombopag showed little or no effect on overall platelet function.

Another worrisome safety issue is the possible long-term exposure effect/s of eltrombopag therapy on bone marrow function. Studies have shown that when megakaryocytes are stimulated, they release TGF-β, which in turn causes a reversible increase in reticulin deposition.[6364] Animal studies have shown, administration of second-generation thrombopoeitic growth factors of causing extensive bone marrow fibrosis, osteosclerosis and extramedullary hematopoiesis-a picture similar to human myelofibrosis.[6566] In the only study[67] in human subjects in which routine bone marrow analysis was performed to determine the effects of first-generation thrombopoietic growth factors, 8 of 9 rhTPO-treated patients and two of six control patients had increased bone marrow reticulin staining. Because of the almost lack of experience with first-generation thrombopoietic growth factors, more long-term exposure studies are needed to specifically explore the effects of second-generation thrombopoietic growth factors on bone marrow function in human subjects. [68] It is pertinent to mention here that both, thromboembolic events in high risk patients, and potentially reversible increases in bone marrow reticulin have been reported with romiplostim (AMG-531), another TPO peptide mimetic.[69] There are reports of rebound worsening of thrombocytopenia as well as increased blast formation, upon discontinuation.[70] Some avoidable interactions with concomitant administration of antacids (containing aluminum and magnesium) and high-calcium food-both causing significant reductions in systemic absorption of eltrombopag have also been reported in the literature.[71]

CONCLUSION

The ultimate aim of treating thrombocytopenia in HVC-positive cases is not to normalize the platelet counts,[72] but to attain and maintain a safe hemostatic level that avoids hemorrhage on one hand and thrombosis on the other. Although more studies are needed to validate true indications, dosage schedule, therapeutic efficacy and safety profile of eltrombopag adjunct therapy, it appears that it is an effective[73] and relatively safe treatment modality (at least in short-term usage) for managing thrombocytopenia in HVC-positive CITP cases. Its main advantage being possible avoidance of interferon dose reductions or interruptions.[74]

Eltrombopag

Drug chart