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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 1  |  Page : 76-81

Effect of direct-acting antiviral agents on hepatitis C virus-associated thrombocytopenia


1 Department of Internal Medicine, Menoufia University, Menoufia, Egypt
2 Internal Medicine Department, Menoufia Liver Institute, Menoufia University, Menoufia, Egypt
3 Department of Community and Public Health, Faculty of Medicine, Menoufia University, Menoufia, Egypt
4 Haematolgy and Haemato-Oncology Hospital, Maady Armed Forces Medical Compound, Cairo, Egypt

Date of Submission18-Feb-2018
Date of Decision17-Mar-2019
Date of Acceptance23-Mar-2019
Date of Web Publication25-Mar-2020

Correspondence Address:
Aly M El-Kholy
Sahil Algawabir Village, Al Shohadaa City, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_55_19

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  Abstract 

Objectives
To evaluate the effect of direct-acting antiviral agents (DAAs) on hepatitis C virus (HCV)-associated thrombocytopenia.
Background
The prevalence of thrombocytopenia in HCV infection ranged from 0.16 to 45.4%. The pathophysiology of HCV-associated thrombocytopenia is poorly understood and multifactorial. Cellular immunity has an important role. Antiplatelet antibodies are common. Production of thrombopoietin may be reduced. Infection of megakaryocytes with HCV may impair platelet production. Clearance of HCV with DAA is expected to restore innate functions of the hepatocytes and immune system reconstitution.
Patients and methods
This was a prospective study on 104 patients with HCV-associated thrombocytopenia receiving DAA (sofosbuvir and daclatasvir); the selected patients were followed up every 4 weeks during antiviral therapy, and at 24 weeks, clinically, and by complete blood count.
Results
The results show that the platelet counts initially decreased on starting the antiviral treatment, then increased gradually and steady during and after the treatment. Thirty-four patients obtained a normal platelet count of more than 150 000 × 103/mm3 at 24 weeks of starting the treatment, and 72 patients obtained a platelet count of more than 100 000 × 103/mm3 at 24 weeks of starting the treatment. There was a significant correlation with the Child–Pugh class, and FibroScan score, and no significant correlation with splenomegaly.
Conclusion
DAA therapy is an effective and safe treatment, and is recommended as a first-line treatment for HCV-associated thrombocytopenia. The main postulated mechanism of HCV-associated thrombocytopenia is the immune-mediated effects of HCV, and DAA therapy has the ability of immune system reconstitution.

Keywords: antiviral agents, hepatitis C virus, immunity, platelet, thrombocytopenia


How to cite this article:
El-Kholy AM, Shoeib SA, Zagla HA, Abdelhafez MA, Abdelhamid AE, Kasemy ZA, Abdelmohsen EA. Effect of direct-acting antiviral agents on hepatitis C virus-associated thrombocytopenia. Menoufia Med J 2020;33:76-81

How to cite this URL:
El-Kholy AM, Shoeib SA, Zagla HA, Abdelhafez MA, Abdelhamid AE, Kasemy ZA, Abdelmohsen EA. Effect of direct-acting antiviral agents on hepatitis C virus-associated thrombocytopenia. Menoufia Med J [serial online] 2020 [cited 2020 Mar 30];33:76-81. Available from: http://www.mmj.eg.net/text.asp?2020/33/1/76/281314




  Introduction Top


The prevalence of hepatitis C virus (HCV) infection worldwide was estimated at 1% in 2015 and this means that around 71 million people worldwide are still considered to be infected[1]. The burden of HCV infection in Egypt is very high. About 15% of the adult population was seropositive for HCV in 2015 and about 11.9% in 2018[2],[3]. Most HCV-infected cases are subclinical, leading to eventual chronic liver disease that can lead to chronic inflammation of the liver and progressive fibrosis and cirrhosis. Further, 25% of patients can develop hepatocellular carcinoma[4]. The prevalence of thrombocytopenia in patients with chronic HCV infection ranged from 0.16 to 45.4%, and more than 50% of the studies reported a prevalence of 24% or more[5]. It is confirmed now that cellular immunity has an important role in the pathophysiology of HCV infection, while different cell factors are also involved[6]. Different lymphocyte subgroups like the effector T-cells, regulatory T-cells, and cytotoxic T-cells also play an important role in HCV infection[7]. The pathophysiology of HCV-associated thrombocytopenia is poorly understood and multifactorial. The HCV structural protein E2 activates polyclonal B cells by binding to CD81, predisposing to clonal expansion of IgM +k+_IgDlow/ CD21low CD27+B cells[8]. Antiplatelet glycoprotein antibodies are common, even without thrombocytopenia. Antiviral antibodies, cross-reactive with GPIIIa, have been identified[9]. Therapeutic clearance of HCV with the direct-acting antiviral agents (DAAs) is expected to restore innate functions of hepatocytes in vivo. In support of this notion, DAA therapy was reported to rapidly decrease inflammation in the livers of mice with humanized livers, a finding that was not associated with interferon (IFN)α/ribavirin therapy[10]. The aim of this study is to evaluate the effect of DAA [sofosbuvir (SOF) and daclatasvir] therapy on HCV-associated thrombocytopenia, and tracking the platelet level changes during and after treatment of HCV infection. To our knowledge, this is the first study of this issue in Egypt.


  Patients and Methods Top


This was a prospective study on 104 patients with HCV-associated thrombocytopenia receiving DAA (SOF and daclatasvir) in Menoufia University Hospitals and National Liver Institute. A signed written informed consent was taken from all patients before starting treatment and the study was approved by the ethics committee of Menoufia University. All selected patients were subjected to the following: thorough history taking, clinical examination, laboratory tests such as hepatitis seromarkers for HCV (anti-HCV Ab), hepatitis B virus; HBs Ag, and HIV (anti-HIV Ab) using the ELISA technique, HCV RNA by nested quantitative PCR by IU/ml, and complete blood count (CBC). Thrombocytopenia, defined as a platelet count of less than 150 000/mm3, liver biochemical profile (LBP): transaminases; aspartate aminotransferase, and alanine aminotransferase, serum albumin, total bilirubin, prothrombin concentration, and international normalized ratio, kidney function tests (blood urea and serum creatinine), α-fetoprotein, antinuclear antibody, thyroid-stimulating hormone, serum Helicobacter pylori antibodies, stool H. pylori antigens, abdominal ultrasonography, and Fibroscan 502 (Echosens, Paris, France). All patients were followed up every 4 weeks during antiviral therapy up to 12 weeks (Sustained virologic response (SVR) 12), and at 24 weeks (SVR24), clinically by weekly symptoms checklist, and by CBC. PCR for HCV RNA was done at start of therapy and at 24 weeks of therapy. Inclusion criteria: adult (≥18 years old) patients, documented HCV infection by positive anti-HCV Ab and positive PCR, and documented HCV-associated thrombocytopenia by CBC. The following were excluded from the study: concomitant hepatitis B virus or HIV infection,history of IFN therapy, hepatocellular carcinoma, autoimmune diseases, endocrinal diseases, H. pylori infection, decompensated chronic liver disease (Child–Pugh class C), advanced fibrosis (FibroScan F4), and patients with pancytopenia. The patients were divided into seven groups according to the presence or absence of splenomegaly, Child–Pugh class (A and B), and FibroScan score (F1, F2, and F3). The platelet count changes were traced for all patients during and after antiviral therapy, and then the different groups were compared regarding baseline liver profile, baseline platelet count, platelet count changes during and after the treatment, and platelet count at 12 weeks after the end of treatment (SVR24). The results were statistically analyzed by SPSS, version 22 (SPSS Inc., Chicago, Illinois, USA). Mann–Whitney, Kruskal–Wallis, and Friedman tests were used for nonparametric data. Spearman and Pearson correlation tests were used for detecting the strength and direction of association between variables. P value less than 0.05 is considered significant.


  Results Top


The mean ± SD of the baseline platelet count for the studied patients is 92.78 ± 25.38; the mean ± SD platelet count at 4 weeks of starting the antiviral treatment is 87.98 ± 27.77; the mean ± SD platelet count at 8 weeks of starting the antiviral treatment is 93.56 ± 33.09; the mean ± SD platelet count at 12 weeks of starting the antiviral treatment (end of the treatment) (SVR12) is 116.20 ± 40.17, and the mean ± SD platelet count at 24 weeks of starting the antiviral treatment (12 weeks after ending the treatment) (SVR24) is 125.98 ± 44.21. This shows that the platelet counts initially decreased on starting the antiviral treatment, and then increased gradually and steady during and after the treatment. Of the patients, 34 patients obtained normal platelet count of more than 150 000 × 103/mm3 at 24 weeks of starting the treatment (32% of patients), and 72 patients obtained a platelet count of more than 100 000 × 103/mm3 at 24 weeks of starting the treatment (69% of patients) [Table 1] and [Graph 1].
Table 1: Platelets of the studied patients

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Comparison between patients with splenomegaly and patients without splenomegaly, regarding the baseline platelet count and platelet count changes during and after the antiviral therapy: Although the platelet count was lower in patients with splenomegaly than those without splenomegaly, there was no significant difference between the two groups. During the treatment there was a significant difference between the two groups only at 8 weeks from starting the antiviral therapy, then there was no significant difference between the two groups at 12 or 24 weeks, but there was a lower platelet count and slower changes in patients with splenomegaly than patients without splenomegaly [Table 2].
Table 2: Distribution of platelets of the studied patients regarding splenomegaly

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Comparison between patients with Child–Pugh A class, and patients with Child–Pugh B class, regarding the baseline platelet count and platelet count changes during and after the antiviral therapy: There was a significant difference between the two groups regarding the baseline platelet count. During the treatment there was a significant difference between the two groups at 8 weeks from starting the antiviral therapy, with lower platelet count and slower changes in patients with Child–Pugh B than patients with Child–Pugh A. Also, there was a significant difference between the two groups regarding the end-platelet count at 24 weeks [Table 3].
Table 3: Distribution of platelets of the studied patients regarding the Child-Pugh classification

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Regarding the fibrosis stages (F1, F2, and F3): There was a significant difference between the three groups at all time points (0, 4, 8, 12, and 24 weeks) regarding the platelet counts; the platelet count changes and end-platelet counts were higher in patients with F1 than patients with F2 than patients with F3 [Table 4].
Table 4: Distribution of platelets of the studied patients regarding fibrosis stages

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  Discussion Top


The aim of this study was to evaluate the effect of DAA (SOF and daclatasvir) therapy on HCV-associated thrombocytopenia, and tracking the platelet level changes during and after treatment of HCV infection. Our results are in agreement with Feld et al.[11] and Foster et al.[12] who found that patients with HCV-associated thrombocytopenia and fibrosis have attained more than 90% SVR with DAAs even if in a proportion lower in respect to patients with a normal platelet count. Thus, DAAs may be continued most of the times without interruption and thrombopoietin mimetics would be helpful only with severe thrombocytopenia (such as a platelet count of <25 000/mm). Bachofner et al.[13] confirmed improvement in platelet countwith DAA therapy, and found that in any case, by the time, thrombocytopenia improves following SVR obtained with any antiviral therapy. Recently, a multidisciplinary consensus and evidence-based recommendations on the management of HCV extrahepatic manifestations have been proposed, and suggested considering DAA as a first-line treatment for HCV-mixed cryoglobulinemia[14]. On the other hand, Lee et al.[15] reported that DAA therapy in one patient precipitated idiopathic thrombocytopenic purpura (ITP) refractory to various treatment modalities and it required several weeks of therapy with multiple platelet transfusions, intravenous immunoglobulin, steroids, and romiplostim to achieve a stable platelet count of 40 000/mm3 with no signs of bleeding. However, this is only one case describing any relation of DAA with thrombocytopenia. Also, it is known that DAAs are supposed to improve thrombocytopenia related to hepatitis C infection but may not ameliorate thrombocytopenia related to cirrhosis or portal hypertension. On the basis of several papers that have reported a strong correlation between spleen size and thrombocytopenia[16], platelet destruction/sequestration as a result of splenomegaly caused by portal hypertension has been considered to be the most important determinant. On the other hand, splenectomy or portal vein shunting does not necessarily normalize the platelet count[17], suggesting that factors other than splenomegaly are also operative in reducing the platelet count during liver fibrosis. Very interesting results were found by Adinolfi LE et al.[18] who compared platelet counts between NAFLD and HCV chronic liver disease (CLD). The platelet counts in NAFLD were significantly higher than in CLD-HCV at all equivalent grades of fibrosis. This means there are other nonliver related factors that might be associated with the decrease in platelet count in CLD-HCV. Regarding the postulated thrombopoietin dysfunction mechanism, Lee et al.[15] described romiplostim use in a case of resistant ITP after DAA therapy. Another study by Jabbour Net al.[19] in 35 patients with chronic liver disease and thrombocytopenia secondary to HCV infection showed more than three-fold increase in mean platelet count from the baseline after 3 weeks of therapy. Eltrombopag has been also found to be safe and effective in the management of HCV-related thrombocytopenia[20]. But in this study, thrombopoietin receptor agonists were not needed for any patients. This can be explained by the differences in the study designs as we excluded patients with advanced fibrosis and patients with Child–Pugh C class in this study, and this means that in compensated patients the main mechanism of HCV-associated thrombocytopenia is the immune-based effects of HCV infection. Nagamine et al.[21] assumed that chronic infection with hepatitis C virus may produce a significant autoimmune reaction if compared with CLD states due to other etiological factors. Nagamine et al.[21] also isolated HCV-RNA from bone marrow megakaryocytes of patients with HCV infection, but not in patients with hepatitis B or control patients. Pockros et al.[22] reported that HCV-RNA was detected in platelets from patients with ITP-associated HCV infection but not in those without ITP. DAA-mediated viral clearance also reversed the activated NK cell phenotype observed in patients with chronic HCV[23]. This was associated with improved NK cell degranulation on in-vitro stimulation with IFNα[24]. DAA treatment with a combination of faldaprevir (NS3 protease inhibitor) and deleobuvir (non-nucleoside NS5B polymerase inhibitor) with or without ribavirin led to a rapid restoration of the in-vitro proliferative capacity of HCV-specific CD8 T cells[25]. For immune reconstitution after curative DAA therapy, it is likely that viral elimination will reduce intrahepatic inflammation, and will reconstitute innate immune mediators such as NK, but there will be a very minimal effect on MAIT cells. Very limited data suggest reduced activation of bulk lymphocytes after DAA therapy[26]. As regards the initial drop in the platelet count at 4 weeks of starting the DAA therapy, it has been presumed that the fast-driven HCV clearance could provoke an abrupt cessation of antigen stimulation, causing a rapid imbalance in immune control, especially in cases of advanced liver disease. Covini et al.[27] reported the case of a woman with chronic hepatitis C and ITP who developed autoimmune hepatitis during antiviral therapy with ledipasvir/SOF. The onset of acute hepatitis rose 2 weeks after starting treatment with ledipasvir/SOF when HCV-RNA tested negative. It has been suggested that rapid elimination of HCV might favor a dysregulation of immune surveillance through a variety of mechanisms. Sise et al.[28] have described three cases of lupus-like immune complex glomerulonephritis with 'full house' immunofluorescence in patients with cirrhosis who were treated with IFN-free all-oral DAA regimens. It is possible that this autoimmune phenomenon represents an immune reconstitution syndrome. These findings raise the possibility that an autoimmune diathesis was unmasked with the removal of HCV, even in the absence of IFN or RBV use. It is tempting to speculate, given the known effects of chronic HCV on suppression of host IFN responses, that removal of viral antigen in otherwise predisposed patients may elicit sensitivity to endogenous IFN effects and resultant unmasking of autoimmunity[29]. Our results confirm the fact that splenomegaly may increase the rate of platelet clearance, but it is not the main cause of HCV-associated thrombocytopenia. Several studies have shown an inverse correlation between the spleen size and platelet count in chronic HCV patients[30]. But splenomegaly and platelet sequestration, or hypersplenism, is observed in only 11–55% of patients with cirrhosis and portal hypertension[31] and, therefore, does not explain all cases of thrombocytopenia in chronic HCV infection[32]. The Ahmed et al.[33] study interestingly showed no correlation between platelet count, MELD score, and spleen size. Our results are in agreement with the El-Sherif et al.[34] results who found that patients with child paugh turcotte score (CPT) class C had a higher baseline international normalized ratio and bilirubin levels, and lower baseline albumin and platelet count than those with CPT class B. Forns[35] examined the relationship between laboratory test values and liver fibrosis in 351 chronic hepatitis C patients. It became evident that platelets (PLT), γ-GTP, age, and total cholesterol are closely related with liver fibrosis. Wong et al.[36] have found a positive correlation between the APRI score and FibroScan stage, and hence a negative correlation between the platelet count and the FibroScan stage. Mawatari et al.[37] reported on the relationship between liver stiffness (as assessed by transient elastography) and the platelet count in CLD-HCV and NAFLD and found the same results.


  Conclusion Top


We aimed in this study to evaluate the effect of DAA (SOF and daclatasvir) therapy on HCV-associated thrombocytopenia, and to track the platelet level changes during and after treatment of HCV infection. On the basis of current results we found that HCV-associated thrombocytopenia is more common in middle-aged women. The platelet count is expected to decrease initially on starting the DAA antiviral treatment, and then increases gradually and steady during and after the treatment. DAA therapy in patients with HCV-associated thrombocytopenia and compensated liver disease is safe with platelet count improvement in most cases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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