1
Accepted Article
Impact of Hepatitis E Virus Seropositivity on Chronic Liver Disease in Cancer Patients with Hepatitis C Virus Infection1
Andreas Kyvernitakis,1 Mahnaz Taremi,1 Boris Blechacz,2 Jessica Hwang,3 Ying Jiang,1 Parag
1
Mahale1 and Harrys A. Torres1
Department of Infectious Diseases, Infection Control and Employee Health, 2Department of
Gastroenterology, Hepatology and Nutrition, 3Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Corresponding author: Harrys A. Torres, MD, Department of Infectious Diseases, Infection Control and Employee Health, Unit 1460, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030. Telephone: +1 713-792-6503; Fax: +1 713-745-6839; E-mail: [email protected].
Running title: HEV seropositivity in HCV-infected cancer patients
Manuscript word count: 1,564 Abstract word count: 184
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/hepr.12460
This article is protected by copyright. All rights reserved.
2
Accepted Article
Presented in part at the Liver Meeting® 65th Annual Meeting of the American Association for the
Study
of
Liver
Diseases,
November
7-11,
2014,
This article is protected by copyright. All rights reserved.
Boston,
MA
3
Accepted Article
Abstract
Background and Aims: Immunocompromised patients can develop chronic hepatitis E virus (HEV) infection and progress to cirrhosis. Hepatitis C virus (HCV) infected cancer patients who have received chemotherapeutic agents experience accelerated liver fibrosis progression. Our
aim was to investigate the prevalence and impact of HEV seropositivity on liver-related outcomes in HCV-infected cancer patients. Methods: As part of a prospective study of HCV-infected cancer patients conducted at our center, we investigate the characteristics associated with progression of their liver disease. Results: Of the 115 patients tested, 13 (11%) were positive for HEV IgG. HEV seropositivity was associated with advanced age (p=0.004), race (p=0.02), place of birth outside the United States (p=0.021), cirrhosis (p=0.027), history of reused needles/syringes during massive vaccination campaigns (p=0.015), and coronary artery disease (p=0.039). Overall, 47 (41%) of the patients had cirrhosis. Factors independently associated with cirrhosis were male sex (OR, 2.8; p=0.028) and HEV seropositivity (OR, 4.1; p=0.032). Conclusions: HEV seropositivity is present in 11% of HCV-infected cancer patients and seems to be associated with cirrhosis. Our results suggest that HEV screening should be implemented in HCV-infected patients with cancer.
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4
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Key words Hepatitis E virus Hepatitis C virus Cirrhosis Cancer
Immunocompromised
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Accepted Article
5
Introduction The prevalence of hepatitis E virus (HEV) IgG antibodies in the general population in the United States is estimated to be 6%, with increased prevalence in patients with chronic hepatitis C virus (HCV) infection.1-3 HEV is considered an emerging infection in developed countries with significant morbidity in immunocompromised patients. For instance, solid-organ transplant recipients and patients with hematologic malignancies or human immunodeficiency virus infection can develop chronic hepatitis and rapid progression to cirrhosis following acute HEV infection.4 Hepatitis C virus (HCV) infection is a well-known cause of chronic liver disease, including cirrhosis.5 Immunocompromised hosts, including cancer patients with chronic HCV infection who receive chemotherapeutic agents, can experience accelerated progression of liver fibrosis.6, 7 The long-term effect of HEV/HCV co-infection in this high-risk population has yet to
be studied. Therefore, we sought to determine the prevalence and impact of HEV seropositivity on liver-related outcomes in HCV-infected cancer patients.
Methods
As part of a prospective observational study of cancer patients with chronic HCV
infection conducted at our center, characteristics associated with the development of chronic liver disease, including co-infections with other hepatotropic viruses, are investigated. Patients enrolled from November 2012 to July 2014 were included in this study. This study was approved by the Institutional Review Board at MD Anderson Cancer Center. Chronic HCV infection was defined as the presence of detectable HCV RNA in HCV-
seropositive patients. Cirrhosis was diagnosed by biopsy, combined evidence from noninvasive
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6
Accepted Article
fibrosis markers using the FIBROSpect II test (Prometheus Laboratories, San Diego, CA, USA), radiologic hepatic morphology and clinical manifestations of cirrhosis. Patients were tested for the presence of IgG antibodies against HEV using the recomWell HEV IgG enzyme immunoassay (Mikrogen GmBH, Frankfurt, Germany). Patients positive for HEV IgG were also tested for the presence of HEV IgM antibodies. Patient demographics, risk factors for acquisition of hepatitis viruses, and other factors contributing to liver disease progression (body mass index, cancer diagnosis, alcohol consumption, tobacco use, estimated years of HCV infection, coinfection with other hepatitis viruses, and history of chemotherapy) were analyzed, and a comparative analysis of HEV seropositive and seronegative patients was conducted. Patients were then assigned to two groups according to their liver disease status, and
factors associated with cirrhosis were investigated. Categorical variables were compared using the chi-square test or Fisher exact test. Continuous variables were compared using the Wilcoxon rank-sum test. Logistic regression modeling was used to identify predictors of cirrhosis. All
covariates with p values less than 0.2 in univariate analysis were included in the initial multivariable model and then the full model was reduced to the final model using a backward elimination procedure. All tests were two-sided tests with a significance level of 0.05. The statistical analyses were performed using SAS version 9.3 (SAS Institute Inc., Cary, NC).
Results
We prospectively evaluated a total of 115 patients. Thirteen (11%) of them tested positive
for HEV IgG, but none of them tested positive for HEV IgM. HEV seropositivity was associated with advanced age (median, 66 years versus 60 years in HEV-seronegative patients; p=0.004), race (p=0.02), place of birth outside the United States (p=0.021), cirrhosis (p=0.027), history of
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7
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reused needles or syringes during massive vaccination campaigns (p=0.015), and coronary artery disease (p=0.039) (Table 1). All HEV-seropositive patients and 80% of the HEV-seronegative patients had at least one potential percutaneous exposure to infected blood, such as intravenous drug use, history of reused needles or syringes, tattoos, and blood transfusion (p=0.12). Overall, 47 (41%) of the patients had cirrhosis. Cirrhosis was associated with advanced
age (median, 61 years versus 59 years in non-cirrhotic patients; p=0.022), male sex (p=0.029), and HEV seropositivity (p=0.027) (Table 2). There were no differences in alcohol consumption, history of chemotherapy use, estimated years of HCV infection, or history of HCV treatment between these two groups. The only factors independently associated with cirrhosis were male sex (odds ratio [OR], 2.8 [95% confidence interval (CI), 1.1-6.8]; p=0.028) and HEV seropositivity (OR, 4.1 [95% CI, 1.1-14.7]; p=0.032).
Discussion HCV infection is a common cause of progressive liver disease, and heavily
immunocompromised patients with chronic infection can experience accelerated progression to cirrhosis.8,
9
On the other hand, HEV infection is generally self-limited in otherwise healthy
individuals but is associated with a high rate of liver disease progression in immunosuppressed patients.4, 10 Here, we report a prevalence of HEV seropositivity of 11% in cancer patients with
chronic HCV infection, in contrast to 6% in the general United States population.1 There are several scenarios that could explain the HEV seropositivity in our study. First,
immunity to HEV following a past infection that has subsided in the presence of chronic HCV infection. Second, chronic HCV/HEV co-infection. Last, acute HEV over chronic HCV infection.
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8
Accepted Article
In developing countries, HEV infection is mainly transmitted through the fecal-oral route,
whereas in developed countries it is either locally acquired through meat consumption (autochthonous) or by recent travel in HEV endemic countries.1 In agreement with the National
Health and Nutrition Evaluation 2009 - 2010 Survey data, we also identified increasing age and country of birth outside the United States as factors associated with HEV seropositivity.1 The effect of increasing age on HEV seropositivity can be due to the increase in prevalence over time, and more systematic screening in this patient population. At the same time, it is possible that some of our patients who were born outside of the US acquired the infection in their country of origin.
One study conducted in the US found that the prevalence of HEV antibodies was
increased in patients with chronic liver disease, the majority of whom had chronic HCV infection.2 These findings come in agreement with our results, but whether they reflect common transmission routes for HEV and HCV infections in some cases is unknown. The fact that HEVseropositive patients were more likely than HEV-seronegative patients to have a history of reused needles or syringes has not been reported and should be considered when assessing risk factors for this infection. Generally, severely immunocompromised patients such as organ transplant recipients are
at high risk for HEV infection.11 In our study, we did not observe differences in HEV
seroprevalence between patients with solid tumors, hematologic malignancies or stem cell transplant recipient, probably due to the small sample size of HEV infected patients included in the study.
In a multicenter study of organ transplant recipients, conducted in Europe and the United
States, more than 60% of patients infected with HEV developed chronic infection, and 10% of
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Accepted Article
them developed cirrhosis within the ensuing 2 years.4 Interestingly, the authors of this study noticed a high percentage of false-negative HEV IgG results, in patients with chronic HEV infection (defined as detectable HEV RNA by PCR), indicating that the actual prevalence of HEV might be even higher in immunocompromised patients. Recently, one study that used 3 different assays to confirm HEV seropositivity, also found an association with HEV and chronic liver disease of viral etiology, the majority being due to HCV.12 Importantly, our study identifies HEV seropositivity as an independent prognostic factor for cirrhosis in cancer patients with chronic HCV infection. These findings suggest that HEV could be an additional factor associated with accelerated fibrogenesis in this patient population. In agreement with our data, a study recently conducted in Spain, reported a high seroprevalence of HEV antibodies in patients with cirrhosis, particularly those who developed cirrhosis after liver transplantation.13 Another study, this one conducted in India, showed also that cirrhosis was associated with HEV infection.14 Ribavirin monotherapy has been successfully used in the treatment of chronic HEV
infection.15 Since this agent is still used in treatment combinations for HCV infection, treatment with ribavirin-based therapy may eradicate both infections simultaneously.16 Previous studies linked male sex with faster progression to cirrhosis in patients
chronically infected with HCV.17-19 This effect is independent of both age at HCV infection and alcohol consumption. A suggested mechanism of this effect is an estrogen-dependent halt in fibrogenesis, which is supported by the increased progression of fibrosis in postmenopausal women.18 Advanced age is another important factor in the progression of fibrosis.19 Immune host factors and age-related fibrosis control are the proposed mechanisms of this effect.18, 19 The main limitation of our study was the lack of HEV RNA detection in the serum of
HEV-seropositive patients, to confirm the presence of acute or chronic HEV infection.
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Accepted Article
Qualitative and quantitative tests for HEV RNA are not commercially available in the United States. Additionally, the cause-and-effect relationship between HEV infection and cirrhosis should be interpreted carefully, as we evaluated this study in a cross-sectional manner and cannot provide accurate information on the timing of HEV seroconversion in relation to liver disease progression. Since our hospital is a cancer center, we did not have a non-cancer patient control group. Therefore, our findings cannot be generalized to the general population. Finally, our study lacks detailed information regarding the patients’ amount of alcohol consumption, a major risk factor in liver disease progression.18, 19
Conclusions In conclusion, HEV IgG seropositivity is present in 11% of HCV-infected cancer patients
and seems to be associated with the presence of cirrhosis. The exact pathogenic role of documented chronic HEV infection (detectable HEV RNA) has yet to be determined in HCVinfected cancer patients. If a synergistic effect of HEV infection on such patients is confirmed, ribavirin-containing regimens can be used to treat these curable infections and prevent liver disease progression in suitable candidates. Our results suggest that HEV screening should be implemented in HCV-infected patients with cancer.
Acknowledgements We thank Don Norwood for editorial assistance.
Conflict of Interest
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11
Accepted Article
The authors have nothing to disclose.
References 1.
Ditah I, Ditah F, Devaki P, et al. Current epidemiology of hepatitis E virus infection in
the United States: Low seroprevalence in the National Health and Nutrition Evaluation Survey. Hepatol. 2014;60(3):815-22. 2.
Atiq M, Shire NJ, Barrett A, et al. Hepatitis E virus antibodies in patients with chronic
liver disease. Emerg Infect Dis. 2009;15(3):479-81. 3.
Kuniholm MH, Purcell RH, McQuillan GM, et al. Epidemiology of hepatitis E virus in
the United States: results from the Third National Health and Nutrition Examination Survey, 1988-1994. J Infect Dis. 2009;200(1):48-56. 4.
Kamar N, Garrouste C, Haagsma EB, et al. Factors associated with chronic hepatitis in
patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterol. 2011;140(5):1481-9. 5.
Seeff LB, Buskell-Bales Z, Wright EC, et al. Long-term mortality after transfusion-
associated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group. N Engl J Med. 1992;327(27):1906-11.
6.
Ennishi D, Maeda Y, Niitsu N, et al. Hepatic toxicity and prognosis in hepatitis C virus-
infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis. Blood. 2010;116(24):5119-25. 7.
King PD, Perry MC. Hepatotoxicity of chemotherapy. Oncologist. 2001;6(2):162-76.
This article is protected by copyright. All rights reserved.
12
Borchardt RA, Torres HA. Challenges in managing hepatitis C virus infection in cancer
Accepted Article
8.
patients. World J Gastroenterol. 2014;20(11):2771-6. 9.
Peffault de Latour R, Levy V, Asselah T, et al. Long-term outcome of hepatitis C
infection after bone marrow transplantation. Blood. 2004;103(5):1618-24. 10.
Kamar N, Bendall R, Legrand-Abravanel F, et al. Hepatitis E. Lancet.
2012;379(9835):2477-88. 11.
Legrand-Abravanel F, Kamar N, Sandres-Saune K, et al. Hepatitis E virus infection
without reactivation in solid-organ transplant recipients, France. Emerg Infect Dis. 2011;17(1):30-7. 12.
Samala N, Wright EC, Trenbeath J, et al. Sero-prevalence of Hepatitis E in Patients with
Chronic Liver Disease. Hepatol. 2014;60(S1):948A. 13.
Riveiro-Barciela M, Buti M, Homs M, et al. Cirrhosis, Liver Transplantation and HIV
Infection Are Risk Factors Associated with Hepatitis E Virus Infection. PLoS One. 2014;9(7):e103028. 14.
Kumar Acharya S, Kumar Sharma P, Singh R, et al. Hepatitis E virus (HEV) infection in
patients with cirrhosis is associated with rapid decompensation and death. J Hepatol. 2007;46(3):387-94. 15.
Kamar N, Izopet J, Tripon S, et al. Ribavirin for chronic hepatitis E virus infection in
transplant recipients. N Engl J Med. 2014;370(12):1111-20. 16.
American Association for the Study of Liver Diseases, Infectious Diseases Society of
America, International Antiviral Society–USA. Initial treatment of HCV infection in patients starting treatment. Recommendations for testing, managing, and treating hepatitis C 2014 [4 Sep
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2014]. Available from: http://www.hcvguidelines.org/full-report/initial-treatment-hcv-infectionpatients-starting-treatment. 17.
Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients
with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349(9055):825-32. 18.
de Torres M, Poynard T. Risk factors for liver fibrosis progression in patients with
chronic hepatitis C. Ann Hepatol. 2003;2(1):5-11. 19.
Freeman AJ, Dore GJ, Law MG, et al. Estimating progression to cirrhosis in chronic
hepatitis C virus infection. Hepatol. 2001;34(4 Pt 1):809-16.
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Accepted Article
Table 1 Characteristics of HEV-seropositive and -seronegative cancer patients with chronic HCV infection
Characteristic Median age, years
HEV IgG-positive
HEV IgG-negative
(n=13)
(n=102)
p value
66 (52-77)
60 (31-87)
0.004
7 (54)
16 (16)
0.004
9 (69)
71 (70)
>0.990
(range)
Age >65 years
Male sex Race
0.020
White
5 (38)
59 (58)
Black
4 (31)
31 (30)
0
8 (8)
4 (31)
4 (4)
28.9 (19.7-35.2)
26.0 (14.7-40.2)
0.320
3 (23)
33 (32)
0.750
0
9 (9)
0.590
Hispanic Middle Eastern/Asian
Median BMI (range) Hematologic malignancy Stem cell transplant recipients
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15
11 (85)
72 (71)
HCC
5 (39)
24 (24)
†HCV genotype 1
9 (69)
76/97 (78)
0.490
†HCV genotype non-1
5 (38)
21/97 (22)
0.180
Accepted Article
Solid tumor
‡IL28B
0.510
0.260
CC
4/9 (44)
18/70 (26)
Other than CC
5/9 (56)
52/70 (74)
Cirrhosis
9 (69)
38 (37)
0.027
Steatosis
6 (46)
39 (38)
0.580
0
13 (13)
0.360
37 (23-43)
38 (9-70)
0.360
Portal hypertension Median estimated years of HCV infection (range) Country of birth
0.021
United States
9 (69)
95 (93)
Other
4 (31)
7 (7)
4 (31)
6 (6)
Reused needles or syringes during vaccination campaigns
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0.015
16
5 (38)
44 (43)
0.750
Tattoos
1 (8)
32 (31)
0.110
History of transfusion
7 (54)
33 (32)
0.140
History of HCV
6 (46)
37 (36)
3 (50)
11 (30)
0.370
6 (46)
39/98 (40)
0.660
0
1/98 (1)
>0.990
0
1 (1)
>0.990
5 (38)
14 (14)
0.039
Accepted Article
Intravenous drug use
treatment
achieved SVR
HBV exposure Core IgG antibody Surface antigen
HIV co-infection §Coronary artery disease
BMI, body mass index; HCC, hepatocellular carcinoma; IL28B, interleukin 28B; SVR, sustained virological response after at least 4 weeks off HCV treatment; HBV, hepatitis B virus. †One patient had mixed genotype 1 and 6 HCV infection. ‡Certain data not available. The patient numbers and percentages were adjusted a ccordingly. §Smoking, hypertension, and dyslipidemia did not differ between the groups.
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Table 2 Predictors of cirrhosis in HCV-infected cancer patients
Characteristic Median age, years (range) Age >65 years
Male sex
Univariate
Cirrhotic
Noncirrhotic
(n=47)
(n=68)
p
61 (38-87)
59 (31-75)
0.022
14 (30)
9 (13)
0.029
38 (81)
42 (62)
0.029
Race
0.400
White
28 (60)
36 (53)
Black
11 (23)
24 (35)
Hispanic
3 (6)
5 (7)
Middle Eastern/Asian
5 (11)
3 (4)
25.3 (19.0-
26.4 (14.7-
40.2)
40.2)
†HCV genotype 1
35/44 (80)
50/66 (76)
0.640
†HCV genotype non-1
10/44 (23)
16/66 (24)
0.850
‡Hematologic malignancy
7/18 (39)
28 (41)
0.860
Median BMI (range)
0.610
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Multivariable OR (95% CI)
p value
2.8 (1.1-6.8)
0.028
18
Stem cell transplant
6 (9)
0.740
13/18 (72)
41 (60)
0.350
Steatosis
23 (49)
22 (32)
0.070
History of HCV treatment
23 (49)
20 (29)
0.750
7/23 (30)
7/20 (35)
Accepted Article
3 (6)
recipients
‡Solid tumor
achieved SVR
Alcohol consumption
0.320
Current
16 (34)
29 (43)
Previous
21 (45)
21 (31)
Never
10 (21)
18 (26)
Smoking
40 (85)
49 (72)
0.10
Diabetes
12 (26)
14 (21)
0.53
History of chemotherapy
26 (55)
47 (69)
0.130
Median estimated years of
40 (20-70)
37 (9-65)
0.140
9 (19)
4 (6)
0.027
HCV infection (range) Presence of HEV IgG
§HBV exposure
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4.1 (1.114.7)
0.032
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Accepted Article
Core IgG antibody Surface antigen
18 (38)
27/64 (42)
0.680
1 (2)
0
0.420
BMI, body mass index; SVR, sustained virological response after at least 4 weeks off HCV treatment; HBV, hepatitis B virus.
†One patient had mixed genotype 1 and 6 HCV infection. ‡Patients with HCV-associated hepatocellular carcinoma were not included in the analysis of this variable.
§Certain data were not available. The patient numbers and percentages were adjusted accordingly.
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Accepted Article
Impact of Hepatitis E Virus Seropositivity on Chronic Liver Disease in Cancer Patients with Hepatitis C Virus Infection1
Andreas Kyvernitakis,1 Mahnaz Taremi,1 Boris Blechacz,2 Jessica Hwang,3 Ying Jiang,1 Parag
1
Mahale1 and Harrys A. Torres1
Department of Infectious Diseases, Infection Control and Employee Health, 2Department of
Gastroenterology, Hepatology and Nutrition, 3Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Corresponding author: Harrys A. Torres, MD, Department of Infectious Diseases, Infection Control and Employee Health, Unit 1460, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030. Telephone: +1 713-792-6503; Fax: +1 713-745-6839; E-mail: [email protected].
Running title: HEV seropositivity in HCV-infected cancer patients
Manuscript word count: 1,564 Abstract word count: 184
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/hepr.12460
This article is protected by copyright. All rights reserved.
2
Accepted Article
Presented in part at the Liver Meeting® 65th Annual Meeting of the American Association for the
Study
of
Liver
Diseases,
November
7-11,
2014,
This article is protected by copyright. All rights reserved.
Boston,
MA
3
Accepted Article
Abstract
Background and Aims: Immunocompromised patients can develop chronic hepatitis E virus (HEV) infection and progress to cirrhosis. Hepatitis C virus (HCV) infected cancer patients who have received chemotherapeutic agents experience accelerated liver fibrosis progression. Our
aim was to investigate the prevalence and impact of HEV seropositivity on liver-related outcomes in HCV-infected cancer patients. Methods: As part of a prospective study of HCV-infected cancer patients conducted at our center, we investigate the characteristics associated with progression of their liver disease. Results: Of the 115 patients tested, 13 (11%) were positive for HEV IgG. HEV seropositivity was associated with advanced age (p=0.004), race (p=0.02), place of birth outside the United States (p=0.021), cirrhosis (p=0.027), history of reused needles/syringes during massive vaccination campaigns (p=0.015), and coronary artery disease (p=0.039). Overall, 47 (41%) of the patients had cirrhosis. Factors independently associated with cirrhosis were male sex (OR, 2.8; p=0.028) and HEV seropositivity (OR, 4.1; p=0.032). Conclusions: HEV seropositivity is present in 11% of HCV-infected cancer patients and seems to be associated with cirrhosis. Our results suggest that HEV screening should be implemented in HCV-infected patients with cancer.
This article is protected by copyright. All rights reserved.
4
Accepted Article
Key words Hepatitis E virus Hepatitis C virus Cirrhosis Cancer
Immunocompromised
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Accepted Article
5
Introduction The prevalence of hepatitis E virus (HEV) IgG antibodies in the general population in the United States is estimated to be 6%, with increased prevalence in patients with chronic hepatitis C virus (HCV) infection.1-3 HEV is considered an emerging infection in developed countries with significant morbidity in immunocompromised patients. For instance, solid-organ transplant recipients and patients with hematologic malignancies or human immunodeficiency virus infection can develop chronic hepatitis and rapid progression to cirrhosis following acute HEV infection.4 Hepatitis C virus (HCV) infection is a well-known cause of chronic liver disease, including cirrhosis.5 Immunocompromised hosts, including cancer patients with chronic HCV infection who receive chemotherapeutic agents, can experience accelerated progression of liver fibrosis.6, 7 The long-term effect of HEV/HCV co-infection in this high-risk population has yet to
be studied. Therefore, we sought to determine the prevalence and impact of HEV seropositivity on liver-related outcomes in HCV-infected cancer patients.
Methods
As part of a prospective observational study of cancer patients with chronic HCV
infection conducted at our center, characteristics associated with the development of chronic liver disease, including co-infections with other hepatotropic viruses, are investigated. Patients enrolled from November 2012 to July 2014 were included in this study. This study was approved by the Institutional Review Board at MD Anderson Cancer Center. Chronic HCV infection was defined as the presence of detectable HCV RNA in HCV-
seropositive patients. Cirrhosis was diagnosed by biopsy, combined evidence from noninvasive
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6
Accepted Article
fibrosis markers using the FIBROSpect II test (Prometheus Laboratories, San Diego, CA, USA), radiologic hepatic morphology and clinical manifestations of cirrhosis. Patients were tested for the presence of IgG antibodies against HEV using the recomWell HEV IgG enzyme immunoassay (Mikrogen GmBH, Frankfurt, Germany). Patients positive for HEV IgG were also tested for the presence of HEV IgM antibodies. Patient demographics, risk factors for acquisition of hepatitis viruses, and other factors contributing to liver disease progression (body mass index, cancer diagnosis, alcohol consumption, tobacco use, estimated years of HCV infection, coinfection with other hepatitis viruses, and history of chemotherapy) were analyzed, and a comparative analysis of HEV seropositive and seronegative patients was conducted. Patients were then assigned to two groups according to their liver disease status, and
factors associated with cirrhosis were investigated. Categorical variables were compared using the chi-square test or Fisher exact test. Continuous variables were compared using the Wilcoxon rank-sum test. Logistic regression modeling was used to identify predictors of cirrhosis. All
covariates with p values less than 0.2 in univariate analysis were included in the initial multivariable model and then the full model was reduced to the final model using a backward elimination procedure. All tests were two-sided tests with a significance level of 0.05. The statistical analyses were performed using SAS version 9.3 (SAS Institute Inc., Cary, NC).
Results
We prospectively evaluated a total of 115 patients. Thirteen (11%) of them tested positive
for HEV IgG, but none of them tested positive for HEV IgM. HEV seropositivity was associated with advanced age (median, 66 years versus 60 years in HEV-seronegative patients; p=0.004), race (p=0.02), place of birth outside the United States (p=0.021), cirrhosis (p=0.027), history of
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7
Accepted Article
reused needles or syringes during massive vaccination campaigns (p=0.015), and coronary artery disease (p=0.039) (Table 1). All HEV-seropositive patients and 80% of the HEV-seronegative patients had at least one potential percutaneous exposure to infected blood, such as intravenous drug use, history of reused needles or syringes, tattoos, and blood transfusion (p=0.12). Overall, 47 (41%) of the patients had cirrhosis. Cirrhosis was associated with advanced
age (median, 61 years versus 59 years in non-cirrhotic patients; p=0.022), male sex (p=0.029), and HEV seropositivity (p=0.027) (Table 2). There were no differences in alcohol consumption, history of chemotherapy use, estimated years of HCV infection, or history of HCV treatment between these two groups. The only factors independently associated with cirrhosis were male sex (odds ratio [OR], 2.8 [95% confidence interval (CI), 1.1-6.8]; p=0.028) and HEV seropositivity (OR, 4.1 [95% CI, 1.1-14.7]; p=0.032).
Discussion HCV infection is a common cause of progressive liver disease, and heavily
immunocompromised patients with chronic infection can experience accelerated progression to cirrhosis.8,
9
On the other hand, HEV infection is generally self-limited in otherwise healthy
individuals but is associated with a high rate of liver disease progression in immunosuppressed patients.4, 10 Here, we report a prevalence of HEV seropositivity of 11% in cancer patients with
chronic HCV infection, in contrast to 6% in the general United States population.1 There are several scenarios that could explain the HEV seropositivity in our study. First,
immunity to HEV following a past infection that has subsided in the presence of chronic HCV infection. Second, chronic HCV/HEV co-infection. Last, acute HEV over chronic HCV infection.
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8
Accepted Article
In developing countries, HEV infection is mainly transmitted through the fecal-oral route,
whereas in developed countries it is either locally acquired through meat consumption (autochthonous) or by recent travel in HEV endemic countries.1 In agreement with the National
Health and Nutrition Evaluation 2009 - 2010 Survey data, we also identified increasing age and country of birth outside the United States as factors associated with HEV seropositivity.1 The effect of increasing age on HEV seropositivity can be due to the increase in prevalence over time, and more systematic screening in this patient population. At the same time, it is possible that some of our patients who were born outside of the US acquired the infection in their country of origin.
One study conducted in the US found that the prevalence of HEV antibodies was
increased in patients with chronic liver disease, the majority of whom had chronic HCV infection.2 These findings come in agreement with our results, but whether they reflect common transmission routes for HEV and HCV infections in some cases is unknown. The fact that HEVseropositive patients were more likely than HEV-seronegative patients to have a history of reused needles or syringes has not been reported and should be considered when assessing risk factors for this infection. Generally, severely immunocompromised patients such as organ transplant recipients are
at high risk for HEV infection.11 In our study, we did not observe differences in HEV
seroprevalence between patients with solid tumors, hematologic malignancies or stem cell transplant recipient, probably due to the small sample size of HEV infected patients included in the study.
In a multicenter study of organ transplant recipients, conducted in Europe and the United
States, more than 60% of patients infected with HEV developed chronic infection, and 10% of
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them developed cirrhosis within the ensuing 2 years.4 Interestingly, the authors of this study noticed a high percentage of false-negative HEV IgG results, in patients with chronic HEV infection (defined as detectable HEV RNA by PCR), indicating that the actual prevalence of HEV might be even higher in immunocompromised patients. Recently, one study that used 3 different assays to confirm HEV seropositivity, also found an association with HEV and chronic liver disease of viral etiology, the majority being due to HCV.12 Importantly, our study identifies HEV seropositivity as an independent prognostic factor for cirrhosis in cancer patients with chronic HCV infection. These findings suggest that HEV could be an additional factor associated with accelerated fibrogenesis in this patient population. In agreement with our data, a study recently conducted in Spain, reported a high seroprevalence of HEV antibodies in patients with cirrhosis, particularly those who developed cirrhosis after liver transplantation.13 Another study, this one conducted in India, showed also that cirrhosis was associated with HEV infection.14 Ribavirin monotherapy has been successfully used in the treatment of chronic HEV
infection.15 Since this agent is still used in treatment combinations for HCV infection, treatment with ribavirin-based therapy may eradicate both infections simultaneously.16 Previous studies linked male sex with faster progression to cirrhosis in patients
chronically infected with HCV.17-19 This effect is independent of both age at HCV infection and alcohol consumption. A suggested mechanism of this effect is an estrogen-dependent halt in fibrogenesis, which is supported by the increased progression of fibrosis in postmenopausal women.18 Advanced age is another important factor in the progression of fibrosis.19 Immune host factors and age-related fibrosis control are the proposed mechanisms of this effect.18, 19 The main limitation of our study was the lack of HEV RNA detection in the serum of
HEV-seropositive patients, to confirm the presence of acute or chronic HEV infection.
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Qualitative and quantitative tests for HEV RNA are not commercially available in the United States. Additionally, the cause-and-effect relationship between HEV infection and cirrhosis should be interpreted carefully, as we evaluated this study in a cross-sectional manner and cannot provide accurate information on the timing of HEV seroconversion in relation to liver disease progression. Since our hospital is a cancer center, we did not have a non-cancer patient control group. Therefore, our findings cannot be generalized to the general population. Finally, our study lacks detailed information regarding the patients’ amount of alcohol consumption, a major risk factor in liver disease progression.18, 19
Conclusions In conclusion, HEV IgG seropositivity is present in 11% of HCV-infected cancer patients
and seems to be associated with the presence of cirrhosis. The exact pathogenic role of documented chronic HEV infection (detectable HEV RNA) has yet to be determined in HCVinfected cancer patients. If a synergistic effect of HEV infection on such patients is confirmed, ribavirin-containing regimens can be used to treat these curable infections and prevent liver disease progression in suitable candidates. Our results suggest that HEV screening should be implemented in HCV-infected patients with cancer.
Acknowledgements We thank Don Norwood for editorial assistance.
Conflict of Interest
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Accepted Article
The authors have nothing to disclose.
References 1.
Ditah I, Ditah F, Devaki P, et al. Current epidemiology of hepatitis E virus infection in
the United States: Low seroprevalence in the National Health and Nutrition Evaluation Survey. Hepatol. 2014;60(3):815-22. 2.
Atiq M, Shire NJ, Barrett A, et al. Hepatitis E virus antibodies in patients with chronic
liver disease. Emerg Infect Dis. 2009;15(3):479-81. 3.
Kuniholm MH, Purcell RH, McQuillan GM, et al. Epidemiology of hepatitis E virus in
the United States: results from the Third National Health and Nutrition Examination Survey, 1988-1994. J Infect Dis. 2009;200(1):48-56. 4.
Kamar N, Garrouste C, Haagsma EB, et al. Factors associated with chronic hepatitis in
patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterol. 2011;140(5):1481-9. 5.
Seeff LB, Buskell-Bales Z, Wright EC, et al. Long-term mortality after transfusion-
associated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group. N Engl J Med. 1992;327(27):1906-11.
6.
Ennishi D, Maeda Y, Niitsu N, et al. Hepatic toxicity and prognosis in hepatitis C virus-
infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis. Blood. 2010;116(24):5119-25. 7.
King PD, Perry MC. Hepatotoxicity of chemotherapy. Oncologist. 2001;6(2):162-76.
This article is protected by copyright. All rights reserved.
12
Borchardt RA, Torres HA. Challenges in managing hepatitis C virus infection in cancer
Accepted Article
8.
patients. World J Gastroenterol. 2014;20(11):2771-6. 9.
Peffault de Latour R, Levy V, Asselah T, et al. Long-term outcome of hepatitis C
infection after bone marrow transplantation. Blood. 2004;103(5):1618-24. 10.
Kamar N, Bendall R, Legrand-Abravanel F, et al. Hepatitis E. Lancet.
2012;379(9835):2477-88. 11.
Legrand-Abravanel F, Kamar N, Sandres-Saune K, et al. Hepatitis E virus infection
without reactivation in solid-organ transplant recipients, France. Emerg Infect Dis. 2011;17(1):30-7. 12.
Samala N, Wright EC, Trenbeath J, et al. Sero-prevalence of Hepatitis E in Patients with
Chronic Liver Disease. Hepatol. 2014;60(S1):948A. 13.
Riveiro-Barciela M, Buti M, Homs M, et al. Cirrhosis, Liver Transplantation and HIV
Infection Are Risk Factors Associated with Hepatitis E Virus Infection. PLoS One. 2014;9(7):e103028. 14.
Kumar Acharya S, Kumar Sharma P, Singh R, et al. Hepatitis E virus (HEV) infection in
patients with cirrhosis is associated with rapid decompensation and death. J Hepatol. 2007;46(3):387-94. 15.
Kamar N, Izopet J, Tripon S, et al. Ribavirin for chronic hepatitis E virus infection in
transplant recipients. N Engl J Med. 2014;370(12):1111-20. 16.
American Association for the Study of Liver Diseases, Infectious Diseases Society of
America, International Antiviral Society–USA. Initial treatment of HCV infection in patients starting treatment. Recommendations for testing, managing, and treating hepatitis C 2014 [4 Sep
This article is protected by copyright. All rights reserved.
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2014]. Available from: http://www.hcvguidelines.org/full-report/initial-treatment-hcv-infectionpatients-starting-treatment. 17.
Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients
with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349(9055):825-32. 18.
de Torres M, Poynard T. Risk factors for liver fibrosis progression in patients with
chronic hepatitis C. Ann Hepatol. 2003;2(1):5-11. 19.
Freeman AJ, Dore GJ, Law MG, et al. Estimating progression to cirrhosis in chronic
hepatitis C virus infection. Hepatol. 2001;34(4 Pt 1):809-16.
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Table 1 Characteristics of HEV-seropositive and -seronegative cancer patients with chronic HCV infection
Characteristic Median age, years
HEV IgG-positive
HEV IgG-negative
(n=13)
(n=102)
p value
66 (52-77)
60 (31-87)
0.004
7 (54)
16 (16)
0.004
9 (69)
71 (70)
>0.990
(range)
Age >65 years
Male sex Race
0.020
White
5 (38)
59 (58)
Black
4 (31)
31 (30)
0
8 (8)
4 (31)
4 (4)
28.9 (19.7-35.2)
26.0 (14.7-40.2)
0.320
3 (23)
33 (32)
0.750
0
9 (9)
0.590
Hispanic Middle Eastern/Asian
Median BMI (range) Hematologic malignancy Stem cell transplant recipients
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15
11 (85)
72 (71)
HCC
5 (39)
24 (24)
†HCV genotype 1
9 (69)
76/97 (78)
0.490
†HCV genotype non-1
5 (38)
21/97 (22)
0.180
Accepted Article
Solid tumor
‡IL28B
0.510
0.260
CC
4/9 (44)
18/70 (26)
Other than CC
5/9 (56)
52/70 (74)
Cirrhosis
9 (69)
38 (37)
0.027
Steatosis
6 (46)
39 (38)
0.580
0
13 (13)
0.360
37 (23-43)
38 (9-70)
0.360
Portal hypertension Median estimated years of HCV infection (range) Country of birth
0.021
United States
9 (69)
95 (93)
Other
4 (31)
7 (7)
4 (31)
6 (6)
Reused needles or syringes during vaccination campaigns
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0.015
16
5 (38)
44 (43)
0.750
Tattoos
1 (8)
32 (31)
0.110
History of transfusion
7 (54)
33 (32)
0.140
History of HCV
6 (46)
37 (36)
3 (50)
11 (30)
0.370
6 (46)
39/98 (40)
0.660
0
1/98 (1)
>0.990
0
1 (1)
>0.990
5 (38)
14 (14)
0.039
Accepted Article
Intravenous drug use
treatment
achieved SVR
HBV exposure Core IgG antibody Surface antigen
HIV co-infection §Coronary artery disease
BMI, body mass index; HCC, hepatocellular carcinoma; IL28B, interleukin 28B; SVR, sustained virological response after at least 4 weeks off HCV treatment; HBV, hepatitis B virus. †One patient had mixed genotype 1 and 6 HCV infection. ‡Certain data not available. The patient numbers and percentages were adjusted a ccordingly. §Smoking, hypertension, and dyslipidemia did not differ between the groups.
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Table 2 Predictors of cirrhosis in HCV-infected cancer patients
Characteristic Median age, years (range) Age >65 years
Male sex
Univariate
Cirrhotic
Noncirrhotic
(n=47)
(n=68)
p
61 (38-87)
59 (31-75)
0.022
14 (30)
9 (13)
0.029
38 (81)
42 (62)
0.029
Race
0.400
White
28 (60)
36 (53)
Black
11 (23)
24 (35)
Hispanic
3 (6)
5 (7)
Middle Eastern/Asian
5 (11)
3 (4)
25.3 (19.0-
26.4 (14.7-
40.2)
40.2)
†HCV genotype 1
35/44 (80)
50/66 (76)
0.640
†HCV genotype non-1
10/44 (23)
16/66 (24)
0.850
‡Hematologic malignancy
7/18 (39)
28 (41)
0.860
Median BMI (range)
0.610
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Multivariable OR (95% CI)
p value
2.8 (1.1-6.8)
0.028
18
Stem cell transplant
6 (9)
0.740
13/18 (72)
41 (60)
0.350
Steatosis
23 (49)
22 (32)
0.070
History of HCV treatment
23 (49)
20 (29)
0.750
7/23 (30)
7/20 (35)
Accepted Article
3 (6)
recipients
‡Solid tumor
achieved SVR
Alcohol consumption
0.320
Current
16 (34)
29 (43)
Previous
21 (45)
21 (31)
Never
10 (21)
18 (26)
Smoking
40 (85)
49 (72)
0.10
Diabetes
12 (26)
14 (21)
0.53
History of chemotherapy
26 (55)
47 (69)
0.130
Median estimated years of
40 (20-70)
37 (9-65)
0.140
9 (19)
4 (6)
0.027
HCV infection (range) Presence of HEV IgG
§HBV exposure
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4.1 (1.114.7)
0.032
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Accepted Article
Core IgG antibody Surface antigen
18 (38)
27/64 (42)
0.680
1 (2)
0
0.420
BMI, body mass index; SVR, sustained virological response after at least 4 weeks off HCV treatment; HBV, hepatitis B virus.
†One patient had mixed genotype 1 and 6 HCV infection. ‡Patients with HCV-associated hepatocellular carcinoma were not included in the analysis of this variable.
§Certain data were not available. The patient numbers and percentages were adjusted accordingly.
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