New Microbiologica, 37, 97-101, 2014

Romiplostim for severe in the treatment of chronic hepatitis C virus infection: a new option for clinicians?

Giovanni Buccoliero, Tiziana Urbano, Patrizio Mazza, Francesco Resta, Salvatore Pisconti Oncohaematologic Department, Division of Infectious Disease, “Saint Joseph Moscati” Hospital, Taranto, Italy

Summary

We describe a case of a 64-year-old man with a history of ITP which had required several treatments including , and with chronic hepatitis C virus (HCV) infection untreated due to severe thrombocytopenia. In March 2011, count was 14,000/mmc and a thrombopoietic therapy with romiplostim was initiated at the dose of 2 mcg/kg/week that was increased to 8 mcg/kg/week. At week 32, platelet count was 65,000/mmc and an anti-HCV therapy with peginterferon and ribavirin was then started. At baseline laboratory tests indicated AST 99IU/l, ALT 125UI/l, HCV_RNA 3,220 UI/ml and HCV genotype 2a/2c. An early virological response (EVR) with normalization of transaminases in the course of antiviral therapy, such as a sustained virological response (SVR) after its interruption were recorded. Therefore a satisfactory platelet count (range 54.000-179.000/mmc) at the dose of 4 mcg/week during antiviral therapy, such as at the dose of 2 mcg/kg/week after antiviral interruption (range 65.000-292.000/mmc) was recorded. Romiplostim proved effective and safe in the course of antiviral treatment. Therefore it permitted the start of anti-HCV therapy despite severe thrombocytopenia and also avoided any peg- dosage modification or discontinuation. Further prospective studies in larger patient cohort should be encouraged to validate this strategy.

KEY WORDS: Romiplostim, Thrompocytopenia, HCV treatment.

Received May 30, 2013 Accepted November 12, 2013

Chronic hepatitis C virus (HCV) infection is even in the absence of treatment (Giannini often asymptomatic (80%) but it can evolve to 2006; Louie et al., 2006), and its pathogenesis cirrhosis and/or hepatocarcinoma over time. is probably multifactorial, due either to an The association of pegylated interferon (peg-in- increased peripheral destruction (related to terferon) and ribavirin is currently used as first hypersplenism or immune-mediated mecha- line antiviral therapy to prevent the evolution nisms), or to a reduced production caused by of chronic HCV to end-stage liver disease. Its suppression or decreased hepatic use, however, is often limited by the develop- secretion of (Peck-Radosav- ment of severe side-effects, including haemato- ljevic 2000; Weksler 2007). The presence of logical disorders such as cytopenias and throm- thrombocytopenia can influence the clinician’s bocytopenia (Manns et al., 2006). choice regarding the initiation of anti-HCV In particular, thrombocytopenia is common in therapy, as peginterferon-based therapy may patients with chronic HCV infection (15-70%) worsen thrombocytopenia in 10-50% of cases through down-regulation of thrombopoietin Corresponding author production (Yamane et al., 2008). Giovanni Buccoliero Therefore, dose reduction or discontinuation of Oncohaematologic Department antiviral therapy are required with consequent Division of infectious Disease increased risk of virological failure and viral re- “Saint Joseph Moscati” Hospital Via per Martina Franca - 74100 Statte (Taranto), Italy lapse (McHutchison et al., 2002). E-mail: [email protected] Many therapeutic strategies including oral ste- 98 G. Buccoliero, T. Urbano, P. Mazza, F. Resta, S. Pisconti roids, intravenous immunoglobulin or anti- sis also seems a possible strategy to increase RhDIg, have been studied to treat HCV-related platelet counts without postoperative bleed- thrombocytopenia. Invasive procedures includ- ing or thrombotic complications (Moussa et ing splenectomy or partial splenic embolization al., 2013). No data regarding the usefulness of are also considered an effective, but not always romiplostim in the course of anti-HCV therapy successful, therapeutic approach for thrombo- are currently available, except for anecdotal cytopenia (Sakuraya et al., 2002; Myake et al., reports. In two cases, romiplostim was used to 2008). control a severe interferon-induced thrombo- Currently, new thrombopoietic agents such as cytopenia; in both cases the anti-HCV protocol and romiplostim, which stimulate with PEG-interferon and ribavirin was com- platelet production by a mechanism similar to pleted without dose reduction or discontinua- that of endogenous thrombopoietin, have been tion (Voican et al., 2012). approved for the treatment of chronic immune In a HCV/HIV coinfected patient with persis- thrombocytopenic purpura (ITP) refractory to tent thrombocytopenia, the increased platelet standard therapy (Kuter, 2007). Safety and ef- count by administration of romiplostim was ficacy of long-term treatment with these drugs followed by initiation and maintenance of anti- in chronic ITP has been demonstrated in clini- HCV treatment without interference with the cal trials (Bussel et al., 2009; Shipperus et al., concomitant antiretroviral therapy (Taylor et 2011). Therefore eltrombopag has been shown al., 2012). to achieve and successfully maintain satisfac- Here, we describe the case of a 64-year-old man tory platelet counts in patients with concomi- diagnosed with chronic ITP in 1971 and HCV tant chronic hepatitis C liver disease, in many infection in 1994, who presented to our ob- cases allowing the start of antiviral therapy servation for the management of chronic ITP which was successfully completed (Danish et in March 2011. He had previously undergone al., 2010). splenectomy and blood transfusions for severe A preoperative use of romiplostim for elective thrombocytopenia in 1981. In addition, he had surgical operations in thrombocytopenic pa- been hospitalized for serious bleeding due to tients with chronic hepatitis C and liver cirrho- thrombocytopenia (15.000/ per cubic

HCV-RNA 3/7[ n. x 100 copie/ml 350 Anti-HCV therapy

300 Romiplostim 2-4mcg/kg/w 8 mcg/kg//w 8mcg/kg/w 4mcg/kg/w 2mcg/kg/w 250

200 PLT HCV-RNA 150

100

50

0 04812162024283236404448525660646872768084889296 ZHHNV

FIGURE 1 - Evolution of platelet count during romiplostim use and HCV viremia pre-on-post anti-HCV therapy in a patient wih chronic ITP. Romiplostim for severe thrombocytopenia in the treatment of chronic hepatitis C virus infection 99 millimeter/mmc) in 2007 and then treated with apy); a sustained virological response (SVR, Rituximab for a short period without success. 48 weeks after antiviral therapy discontinua- At the visit, the blood count showed mild leu- tion) was obtained. During antiviral therapy, kocytosis (12.500/mmc), normal hemoglobin platelet counts ranged between 54,000/mmc level (14.5 g/dl) and severe thrombocytopenia and 179,000/mmc (median 101,000/mmc) with (14,000/mmc) and so a thrombopoietic therapy romiplostim at the dose of 4 mcg/kg/week re- with romiplostim at the dose of 2 mcg/kg/week duced at week 12. After anti-HCV therapy in- was started, with weekly platelet count moni- terruption we administered romiplostim at the toring; after 12 weeks, the romiplostim dose dose of 2 mcg/kg/week, maintaining the same was changed into 8 mcg/kg/week. The evolution dose until now and recording a satisfactory of platelet count during romiplostim therapy is platelet count which ranged between 65,000/ shown in Figure 1. mmc and 292,000/mmc (median 141,000/ During routine examinations, he presented mmc). No symptoms or signs of myelofibrosis hypertransaminasemia (>1.5 of normal) HCV_ post treatment were observed. RNA 3,220 UI/ml (PCR TaqMan real time meth- Therefore, the administration of romiplostim od, cut off <16 UI/ml) and HCV genotype 2a/2c. was effective and safe in our patient in the He reported that he had never been treated for course of antiviral treatment, not only allowing HCV because of his history of thrombocytope- the initiation of antiviral therapy despite severe nia ranging from 12,000 to 25,000/mmc. thrombocytopenia but also avoiding any peg- In October 2011, virological status and liver interferon dosage modification or discontinua- function parameters were re-assessed. Labo- tion and thus increasing the probability of SVR. ratory tests indicated elevation of aspartate Patients with chronic HCV infection with aminotransferase (AST 99IU/l), alanine ami- thrombocytopenia (<75,000/mmc) have been notransferase (ALT 125UI/l), gamma-glutamyl routinely excluded from clinical trials of inter- transpeptidase (gamma-GT 81UI/l), mild hy- feron and ribavirin. Although a reduced plate- poalbuminemia (3.6 g/dl), hypergammaglobu- let count is not an absolute contraindication linemia (31.8%), and normal levels of total to treatment with peginterferon and ribavirin, bilirubin (0.63 mg/dl) and alkaline phosphatase product labels advise that caution be used in (62UI/l). Other causes of liver disease were ex- patients with significant thrombocytopenia. cluded. Abdominal ultrasound examination did Typically, thrombocytopenia occurs within the not show suspect hepatic nodules or ascitis. first 8 weeks of therapy, and the manufactur- After 32 weeks on romiplostim treatment plate- ers of peginterferon alfa-2a and alfa-2b rec- let count was 65,000/mmc and an anti-HCV ommend dose reduction for platelet counts therapy based on the combination of peginter- less than 50,000/mmc and discontinuation for feron at reduced dose (Pegasys 135 mcg/week) platelet counts less than 25,000/mmc. (Roche. and ribavirin (Copegus 800 mg/die) was then Prescribed information. Available at www. started. At baseline, AST 89UI/l, ALT 101UI/l, pegasys.com; Shering. Prescribed information. gammaGT 88UI/l, leukocyte count 11,500/mmc, Available at HYPERLINK “http://www.pegin- hemoglobin level 13.6 g/dl were recorded. tron.com” www.pegintron.com). Peginterferon After 4 weeks of anti-HCV therapy, the viral dose reduction, however, is still associated with load became undetectable defining an early a decrease of SVR, indicating the importance of virological response (EVR) and serum levels maintaining a full-dose antiviral therapy (Shiff- of transaminases decreased (AST 63UI/l, ALT man et al., 2007). 59UI/l). Normalization of transaminases and In our patient with a long history of ITP, the ac- gammaGT were recorded at week 8; on HCV quired HCV infection exacerbated the throm- treatment leukocyte count ranged between bocytopenia with a serious hemorrhagic event 7200 and 9100/mmc and hemoglobin levels leading to hospitalization. Therefore, anti-HCV between 9.1-13.1 g/dl. An irritating oral lichen treatment was started not only to avoid liver occurred which was treated with VEA oris with disease progression but also to improve chron- partial relief. HCV-viremia remained below ic ITP. In fact, the feedback between platelet the limit of detection at week 24 (end of ther- count and thrombopoietin release is altered 100 G. Buccoliero, T. Urbano, P. Mazza, F. Resta, S. Pisconti in HCV-related chronic liver disease (Peck- penia in chronic liver disease and pharmacologic Radosavljevic et al., 1998; Giannini et al., 2003; treatment options. Aliment. Pharmacol. 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