Current Opinion in Hematology:
MYELOID BIOLOGY: Edited by David C. Dale
Hepatitis C and neutropenia
Sheehan, Vivien A.a; Weir, Alvab; Waters, Bradfordc
aTexas Children's Hematology Center, Baylor College of Medicine, Houston, Texas
bDivision of Hematology-Oncology, Veterans Affairs Medical Center and University of Tennessee Health Science Center
cDivision of Gastroenterology and Hepatology, Veterans Affairs Medical Center and University of Tennessee Health Science Center, Memphis, Tennessee, USA
Correspondence to Bradford Waters, MD, Medical Service (111), VA Medical Center, 1030 Jefferson Avenue, Memphis, TN 38104, USA. Tel: +1 901 523 8990 ext 6648; fax; 1 901 577 7286; e-mail: email@example.com
Purpose of review: This review describes the pathogenesis and therapeutic implications of neutropenia in patients with hepatitis C.
Recent findings: Mild-to-moderate neutropenia is increasingly recognized as the hepatitis C population has caused increased cirrhosis. Multiple mechanisms for the neutropenia have been postulated, with recent evidence pointing toward a combination of hypersplenism, autoimmunity, and direct viral infection of bone marrow cells. Advances in antiviral therapy are associated with worsened neutropenia and dose modification. Severe neutropenia is underreported and is generally not associated with increased rates of infection.
Summary: Although neutropenia is common in hepatitis C patients it generally has a benign course and may not prohibit antiviral therapy.
Neutropenia, a common finding in patients infected by hepatitis C virus (HCV), significantly affects therapeutic options. The primary cause of neutropenia in any given patient may be due to direct viral cytotoxicity or related to other problems to which the HCV patients are predisposed, namely immune dysregulation, coinfections, splenomegaly, or medication effects. Further study of neutropenia in chronic HCV infections is needed to understand its pathophysiology, infection risk, and best treatment options, both for secondary infections and for the primary chronic HCV infection. Although severe neutropenia has been a contraindication to HCV therapy , case reports have described improvement in severe neutropenia during antiviral therapy . A clear understanding of the risks and potential benefits of treating HCV in the setting of neutropenia is especially relevant given newly approved additional antiviral therapies that increase the potential for cure.
PATHOPHYSIOLOGY OF NEUTROPENIA IN THE SETTING OF CHRONIC HEPATITIS C VIRUS
Multiple causes of HCV-related cytopenias have been postulated, including direct viral inhibition, hypersplenism, and autoimmune processes [3–5]. These same processes may be responsible for the less frequently reported and studied neutropenia. The presence of autoantibodies in chronic HCV patients is exceedingly common; reports of 7–69% of tested patients have some degree of antinuclear antibody (ANA) positivity that raises the possibility of an autoimmune process resulting in neutrophil destruction [6,7]. But the relationship between ANA positivity in chronic HCV and cytopenias is uncertain, and a clear association between autoantibodies and neutropenia has not been made . In a Memphis Veterans Affairs Medical Center (VAMC), two of six severely neutropenic patients demonstrated a positive ANA but only one of 24 patients (4.2%) with minor neutropenia had a positive ANA, suggesting a possible autoimmune connection [9▪]. The wide range of reported ANA positivity between studies and the paucity of studies that also report associated hematologic values make a causative relationship difficult to prove.
Two potential mechanisms for developing autoimmunity have been described. Infection of lymphoid cells by HCV may upregulate apoptosis inhibitors, such as B cell activating factor, and lead to prolonged B cell survival. This, coupled with the chronic stimulation of lymphocytes by ongoing HCV infection, may predispose patients to developing clonal antibodies . Ramon-Casals et al. also implicated an autoimmune cause for the observed cytopenias and increased frequency of autoimmune markers in HCV patients.
VIRUS-MEDIATED EFFECTS IN BONE MARROW
Although hepatitis C replicates primarily in the liver, bone marrow replication has been clearly demonstrated . In one study, the level of HCV viremia in patients was found to correlate directly with the presence of bone marrow HCV RNA [13▪]. In a series of 30 untreated chronic HCV patients subjected to bone marrow biopsy, 53% had HCV RNA in the bone marrow. These patients differed from the 47% with HCV RNA negative bone marrow in that they had higher viral loads, and lower levels of leukocytes, hemoglobin, and platelets. All of the patients with HCV RNA positive bone marrow had morphologic changes, including patchy cellularity, inflammatory lymphocytes, and plasma cells; none of the individuals with HCV RNA negative bone marrow had such morphologic changes [13▪]. Because HCV is able to replicate in bone marrow  and has been found in CD34+ hematopoietic progenitor cells [3,14,15], it is plausible that viral infection of the bone marrow plays a role in virus-associated neutropenia, anemia, and thrombocytopenia.
Other researchers also found bone marrow abnormalities in HCV patients but did not test for the presence of HCV RNA in bone marrow samples. A series of bone marrow biopsies, performed for various peripheral blood abnormalities, in 47 patients with HCV was described by Klco et al.. Eighteen had an absolute neutrophil count less than 1.8 K/μl. None had HIV. The authors found nine patients to have dyserythropoiesis, two to have acute myeloid leukemia, and one to have myelodysplastic syndrome. In our report of six treatment-naive severely neutropenic HCV patients, the three who received bone marrow examinations had no signs of abnormal myelopoesis; one sample was mildly hypocellular. The samples were not tested for HCV RNA [9▪].
VIRUS-MEDIATED EFFECTS ON NEUTROPHILS IN PERIPHERAL BLOOD
Mechanisms have been sought to explain viral-mediated neutrophil damage. Aref et al. demonstrated an increase in neutrophil apoptosis associated with increased caspases 3 and 10, when neutrophils from either normal or HCV-infected individuals were incubated with sera from HCV-infected patients. Tawadrous et al.[18▪] postulated that viral-induced increased expression of RANTES (regulated on activation normal T cell expressed and secreted) and tumor necrosis factor α might be associated with the cytopenias in HCV patients, but no direct connection has been verified experimentally.
The treatment response implications of HCV RNA positive peripheral blood mononuclear cells and bone marrow remain to be elucidated, as well as the relationship between cytopenias, particularly neutropenia, and HCV RNA present in the bone marrow. There is not yet convincing data to recommend that HCV patients with hematologic abnormalities be subjected to bone marrow biopsy. We do not yet know whether the presence of virus in bone marrow alters response to antiviral therapy or increases treatment toxicities. Neutropenia potentially resulting from viral cytotoxicity in bone marrow or peripheral blood cannot currently be distinguished from neutropenia resulting from neutrophil destruction.
SECONDARY CAUSES OF NEUTROPENIA
A number of infectious agents in addition to HCV might lead to neutropenia. Hepatitis C patients are at an increased risk for HIV infections because of similar infecting mechanisms (e.g., transfusions and contaminated needles). Other viral illnesses common to the normal population may produce transient neutropenia. Organisms such as Salmonella, Shigella, and Brucella, and tuberculosis, rickettsia, malaria, and leishmania may produce illness in chronically infected hepatitis C patients and produce neutropenia as well .
Benign ethnic neutropenia is common in patients of African descent. In one series of HCV patients, 14% of African-Americans were excluded from antiviral therapy because of neutropenia (<1.500 K/μl) compared with only 3% in non-African-Americans. African-Americans had neutrophil counts less than 1.200 K/μl in 7% compared with 1% of non-African-Americans .
Many drugs (particularly antithyroid drugs, antipsychotics, and certain antibiotics) may produce neutropenia, either through bone marrow suppression or autoimmune destruction. Tables of drugs that might produce agranulocytosis are readily available. Autoimmune neutropenia may be idiopathic, related to drug exposure, or associated with a coexisting autoimmune disorder such as systemic lupus or rheumatoid arthritis .
Nutritional deficiencies, including vitamin B12 and folic acid, should be considered in all neutropenic patients. Primary bone marrow disorders should also be considered and blood smears reviewed to decide on the level of investigation needed to pursue these diagnoses.
Studies in the United States have shown that the percentage of patients with hepatitis C with cirrhosis has increased from 9% in 1996 to 15% in 2005 . The proportion of chronic hepatitis C with cirrhosis was estimated to be 25% in 2010 and is to reach 45% in 2030 . Hypersplenism is common in long-term hepatitis C patients who have developed portal hypertension from cirrhosis. Hypersplenism commonly produces thrombocytopenia and neutropenia. In their evaluation of hematologic abnormalities within a cohort of cirrhotic patients entering a clinical trial with β blockers, Qamar et al. discovered that 42% of the cirrhotic patients had leukopenia at baseline. In this study, leukopenia was associated with an increased risk of death or transplantation. Although leukopenia correlated with the severity of portal hypertension measured by hepatic venous pressure gradient, this was not felt to be the only cause for leukopenia. Although minor-to-moderate leukopenia is common among cirrhotic patients and probably related to hypersplenism, there is no clear relationship between cirrhosis, spleen size, and severe neutropenia in neutropenic hepatitis C patients [9▪].
INCIDENCE OF SEVERE NEUTROPENIA IN CHRONIC HEPATITIS C VIRUS
Mild cytopenias of minimal clinical significance are frequently reported in the setting of chronic HCV infection, often in the setting of hypersplenism . However, severe neutropenia, defined as an absolute neutrophil count less than 0.500 K/μl, is rarely reported outside of interferon α therapy. Until recently, only two case reports of isolated severe neutropenia in naive patients with chronic HCV had been published [2,11]. Researchers analyzing the GE Healthcare Centricity Electronic Medical Records database for a 5-year period identified 45 690 patients with a laboratory-confirmed diagnosis of HCV and a contraindication for antiviral therapy: 1.2% (557) of patients had an absolute neutrophil count less than 0.750 K/μl [25▪]. In a 2013 published survey of 685 chronic HCV patients in the Memphis VAMC, six patients with severe neutropenia were discovered [9▪]. Such findings indicate that severe neutropenia in the setting of chronic HCV is underreported, underrecognized, and underexamined.
MANAGEMENT OF NEUTROPENIA IN HEPATITIS C VIRUS PATIENTS NOT RECEIVING ANTIVIRAL THERAPY
Most available literature discussing the infectious complication risk of HCV antiviral therapy has demonstrated no clear link between infection risk and neutropenia [26,27]. These findings may be extrapolated to managing treatment-naive HCV-related neutropenia, knowing that prompt, antiviral therapy might ameliorate baseline neutropenia [2,28]. However, the required use of granulocyte colony-stimulating factor (G-CSF) has been associated with side-effects including bone pain, acute lung and vascular injury, and splenic rupture . The use of G-CSF, although not routinely recommended in chronic HCV-related neutropenia , is often effective. In our group of six severely neutropenic patients, two were given GCSF with overall good response, one after developing a cutaneous abscess, the other after recurrent cellulitis [9▪]. Consideration of GCSF is reasonable in severely neutropenic patients with recurrent, serious, or refractory infection.
EFFECTS OF NEUTROPENIA ON TREATMENT ELIGIBILITY AND ABILITY TO TOLERATE ANTIVIRAL THERAPY
Neutropenia in hepatitis C patients is a therapeutic problem as it reduces the number of patients eligible for therapy. In a 2012 study by Giannini et al., the authors used the European association for the Study of the Liver (EASL) clinical guidelines  as criteria for contraindications to antiviral therapy. Contraindications included an absolute neutrophil count less than 1.5 K/μl. Applying the EASL criteria to 1538 patients, the researchers noted neutropenia in 3.2% of patients. Of the 233 patients with cytopenias, including neutropenia, only 40% received antiviral therapy. Of those who were treated, 58% were withdrawn from treatment because of side-effects. Only 37% of patients with preexisting cytopenias achieved sustained viral response, which is lower than in most published HCV studies . Although authors have questioned the exclusion of patients with neutrophils less than 1.5 K/μl, there has not been enough evidence to modify the treatment guidelines. In a study among HCV patients with cirrhosis, 23.4% had to discontinue antiviral therapy because of neutropenia/thrombocytopenia . The presence of cirrhosis clearly affects the incidence of neutropenia in patients receiving antiviral therapy.
As described above, benign ethnic neutropenia among African-Americans has a clinical effect on the treatment of hepatitis C. The combination of underlying neutropenia in African-Americans in the setting of increasing rates of cirrhosis increases the clinical significance of neutropenia in hepatitis C patients. In a multicenter study of US veterans, African-Americans had more severe baseline neutropenia (2.9 vs. 4.1 K/μl) and a reduced dose of interferon (4.7 vs. 1.6%) .
MANAGING NEUTROPENIA IN HEPATITIS C VIRUS PATIENTS DURING ANTIVIRAL THERAPY
Treatment-related neutropenia during antiviral therapy can be managed by dose reduction or by using granulocyte-stimulating agents. Both approaches are controversial, however. Dose reduction might potentially decrease the chance of sustained viral response, defined as the absence of HCV RNA over 6 months following completion of antiviral therapy. Although GCSFs have allowed patients to continue antiviral therapy or return to the optimal dose of treatment, there is limited evidence that using granulocyte colony-stimulating agents improves sustained viral response compared with those patients treated with only dose reduction [35,36]. In a study by Younossi et al., filgrastim was used to treat neutropenia during antiviral therapy for chronic hepatitis C. Filgrastim improved neutropenia from 0.75 + 0.16 to 8.28 + 5.67 K/μl. In this study, low viral load, nongenotype 1, and treatment with growth factors were associated with sustained viral response following hepatitis C therapy. It is possible that treatment with growth factors allowed practitioners to avoid dose reductions, which led to a better outcome.
The 2011 EASL guidelines stated that that there is no clear adverse effect of the neutropenia associated with interferon and ribavirin . Although bacterial infections have been described in more than 20% of HCV patients on antiviral therapy, surprisingly, infections were not associated with the degree of neutropenia. In one series of HCV patients who developed bacterial infections while on antiviral therapy, the frequency of infection was associated with age, diabetes, and cirrhosis but not neutropenia . Another study found 29% of patients on antiviral therapy had neutropenia less than 0.750 K/μl; 5% had less than 0.375 K/μl. However, infections were also not associated with neutropenia . These observations support the recommendation not to use GCSF agents as primary therapy to prevent interferon dose reductions .
The addition of direct antiviral therapy with first-generation protease inhibitors and pegylated interferon and ribavirin has increased the sustained viral response but also the frequency of hematological complications. The addition of boceprevir to pegylated interferon and ribavirin increased the frequency of neutropenia from 13% to 25–27%. Neutropenia of less than 0.5 K/μl was increased from 4% to 6–7% . In a separate study with boceprevir, pegylated interferon, and ribavirin, the frequency of neutropenia (0.500–0.750 K/μl) was increased from 14% to 24–25%. The frequency of severe neutropenia (<0.500 K/μl) was increased from 4% to 6–8% with triple therapy. The use of granulocyte-stimulating agents increased from 6% with double therapy to 8–12% with triple therapy .
The addition of telaprevir to pegylated interferon and ribavirin increased the frequency of anemia but not neutropenia. The frequency of neutropenia was 19% with pegylated interferon and ribavirin and 14–17% with the addition of telaprevir . In a multicenter study of 859 US veterans with hepatitis C, one-third of the patients had to stop triple antiviral therapy by week 24. The frequency of neutropenia was 34% in those treated with boceprevir and 21% in those treated with telaprevir (P = 0.008) .
The future hematological impact of noninterferon-based antiviral treatment remains to be determined. In studies of the nucleotide analog sofosbufir used in combination with pegylated interferon and ribavirin, the frequency of cirrhosis was 17–21%. The frequency of adverse events with neutropenia was 17% compared with 12% in those treated with only pegylated interferon and ribavirin. Among the 17% who developed neutropenia on triple therapy of sofosbuvir, pegylated interferon, and ribavirin, 5% had neutrophil counts less than 0.500 K/μl. Fortunately, in a treatment arm of 256 patients treated with sofosbufir and ribavirin for 12 weeks, no neutropenia was observed .
Managing neutropenia during antiviral therapy should initially focus on dose reduction of interferon (Table 1). Boceprevir, telaprevir, and ribavirin do not require dose modification. G-CSFs are not recommended as first-line agents to prevent neutropenia. If interferon therapy is maintained above the package insert recommendations, then close monitoring of neutrophil counts and G-CSFs can be used. Their role may also be useful in the setting of liver transplantation and for patients with HIV and HCV coinfection. G-CSFs may be required in those patients treated with the combination of direct protease inhibitors, interferon, and ribavirin resulting in neutropenia that does not correct with the dose reduction of interferon .
Potential roles of G-CSFs can be summarized as for:
1. failure to correct neutropenia after interferon dose reduction (to resume therapy and avoid additional reduction) ;
2. neutropenia during therapy in the setting of liver transplantation and HIV/HCV coinfection .
Neutropenia is an increasingly recognized entity in HCV patients. The cause is multifactorial. With the increased rate of cirrhosis, mild-to-moderate neutropenia is anticipated to increase. Fortunately, neutropenia during antiviral therapy has not been associated with increased rates of infection. It is not yet clear whether guidelines should expand the use of antiviral therapy to patients who present with neutrophil counts less than 1.5 K/μl, but this question should be explored. Severe neutropenia in HCV has been underreported and is generally a benign condition.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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hepatitis C; interferon; neutropenia
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