HEPATOLOGY, Vol. 61, No. 6, 2015
CORRESPONDENCE
2117
Reply to “Does Chronic Hepatitis E Virus Infection Exist in Immunocompetent Patients?” We thank Drs. Kamar and Izopet for their interest in our case report on chronic hepatitis E in a patient with a distant history of systemic lupus erythematosus (SLE), and appreciate their comments on this patient’s immune status.1 While we acknowledge that our patient’s history of SLE may have increased her susceptibility to developing chronic hepatitis E virus (HEV), it should be noted that the lupus has long been in remission (double-stranded DNA was negative in 2006, antinuclear antibody (ANA) was negative in 2007, and in 2008 C3 and C4 were both normal and Smith and RNP antibodies were negative), and we feel there is no strong temporal correlation between her medically induced immunosuppression for lupus and the development of her chronic viral hepatitis. Diagnosis of SLE was made in 1973, with prednisone therapy continuing through 1980, along with an initial short course of plaquenil. Transaminase elevations were first noted in 2002, 20 years following cessation of lupus therapy. While our patient did receive two courses of prednisone for presumed autoimmune hepatitis, from October of 2005 through April of 2006 and from March of 2007 through September of 2007, elevated enzymes preceded the steroid courses by 31=2 years. Also of note, flow cytometry of bone marrow aspirate performed in March of 2008 for analysis of atypical lymphs was normal and showed no monoclonal B-cell population, aberrant T-cell phenotype, or deficiency in her CD3-, CD4-, and CD8-
positive cells suggestive of as immunocompromised state. Her peripheral total lymphocyte count has always been normal. The atypical lymphs were likely related to her chronic HEV infection. While we feel that our patient was not immunocompromised during the period of infection with hepatitis E, we welcome Drs. Kamar and Izopet’s suggestions and are in agreement that additional details regarding this patient’s immune status, especially her anti-HEV-specific T-cell response, are warranted and we will pursue further testing. PRIYA GREWAL, M.D. Mount Sinai School of Medicine Recanati/Miller Transplantation Institute New York, NY
References 1. Kamar N and Izopet J. Does chronic hepatitis E virus infection exist in immunocompetent patients? HEPATOLOGY 2015;61:427. C 2015 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27423 Potential conflict of interest: Nothing to report.
Effect of Interferon-Alpha Therapy on Hepatitis D Virus To the Editor: We read with interest the study by Guedj et al.1 describing the dynamics of hepatitis D virus (HDV) and hepatitis B surface antigen (HBsAg) after the commencement of pegylated interferon (IFN)-alpha 2a therapy. This study provides valuable data on this virus, which results in increased morbidity and mortality over hepatitis B virus (HBV) monoinfection. However, their conclusions on where IFN acts on the viral life cycle and their estimate of virion half-life are unlikely to be correct. Their calculations determined a median 8.5-day delay after IFN therapy started before HDV-RNA levels in serum decreased, yet they concluded that IFN impacted only on viral production, rather than new infection. This was less of a conclusion than an assumption given that their mathematical modeling excluded any inhibition of new infection (h 5 0 in their model). In contrast to the slow initial HDV-RNA delay observed in this study, HBV DNA decreases after a few hours with IFN and/or lamivudine therapy in HBV infection.2 Both of these drugs affect HBV virion production. Inhibition of virion production, as observed in the latter HBV study, will quickly affect viremia given that it acts closest to the stage that is renewing virus in serum. In contrast, inhibition of new infection will take a while to manifest itself on virion levels in serum given that a cell infected just before therapy will take some time to produce virus as the infection progresses through its complete replication cycle within that cell. This difference of effect determined by the length of the initial delay before viremia decreases has been observed in human immunodeficiency virus (HIV) by Murray et al.3 Monotherapy that inhibits fusion of a virion with a cell showed a larger initial delay in response than a drug that inhibited a later stage, such as integration of HIV DNA into the cell genome. All of these results and the long delay before HDV RNA
decreases after IFN suggest that this drug impacts on new infection, rather than the much later stage of HDV virion production. If that is correct, then the length of delay indicates that the intracellular infection cycle of HDV or of HBV is, on average, 8.5 days in vivo. It is difficult to be sure which virus life cycle is reflected by this delay because HDV can infect cells that are not already infected with HBV, but requires HBV infection to be able to produce new virus.4 This 8.5-day duration is consistent with a 7.9-day half-life estimate of HBV-infected cells.5 The very long 2.9-day half-life estimate for HDV virions is also unlikely to be correct. Prenylation inhibitor therapy, which acts at the HDV virion packaging stage within an infected cell, resulted in an 85% decrease of HDV RNA in serum of mice after 2 days,6 much faster than would be reflected by a 2.9-day half-life. ASHISH GOYAL, M.S. JOHN M. MURRAY, PH.D. School of Mathematics and Statistics University of New South Wales Sydney, New South Wales, Australia
References 1. Guedj J, Rotman Y, Cotler SJ, Koh C, Schmid P, Albrecht J, et al. Understanding early serum hepatitis D virus and HBsAg kinetics during pegylated interferon-alfa therapy via mathematical modeling. HEPATOLOGY 2014;60:1902-1910. 2. Sypsa VA, Mimidis K, Tassopoulos NC, Chrysagis D, Vassiliadis T, Moulakakis A, et al. A viral kinetic study using pegylated interferon alfa2b and/or lamivudine in patients with chronic hepatitis B/HBeAg negative. HEPATOLOGY 2005;42:77-85.
CORRESPONDENCE
2117
Reply to “Does Chronic Hepatitis E Virus Infection Exist in Immunocompetent Patients?” We thank Drs. Kamar and Izopet for their interest in our case report on chronic hepatitis E in a patient with a distant history of systemic lupus erythematosus (SLE), and appreciate their comments on this patient’s immune status.1 While we acknowledge that our patient’s history of SLE may have increased her susceptibility to developing chronic hepatitis E virus (HEV), it should be noted that the lupus has long been in remission (double-stranded DNA was negative in 2006, antinuclear antibody (ANA) was negative in 2007, and in 2008 C3 and C4 were both normal and Smith and RNP antibodies were negative), and we feel there is no strong temporal correlation between her medically induced immunosuppression for lupus and the development of her chronic viral hepatitis. Diagnosis of SLE was made in 1973, with prednisone therapy continuing through 1980, along with an initial short course of plaquenil. Transaminase elevations were first noted in 2002, 20 years following cessation of lupus therapy. While our patient did receive two courses of prednisone for presumed autoimmune hepatitis, from October of 2005 through April of 2006 and from March of 2007 through September of 2007, elevated enzymes preceded the steroid courses by 31=2 years. Also of note, flow cytometry of bone marrow aspirate performed in March of 2008 for analysis of atypical lymphs was normal and showed no monoclonal B-cell population, aberrant T-cell phenotype, or deficiency in her CD3-, CD4-, and CD8-
positive cells suggestive of as immunocompromised state. Her peripheral total lymphocyte count has always been normal. The atypical lymphs were likely related to her chronic HEV infection. While we feel that our patient was not immunocompromised during the period of infection with hepatitis E, we welcome Drs. Kamar and Izopet’s suggestions and are in agreement that additional details regarding this patient’s immune status, especially her anti-HEV-specific T-cell response, are warranted and we will pursue further testing. PRIYA GREWAL, M.D. Mount Sinai School of Medicine Recanati/Miller Transplantation Institute New York, NY
References 1. Kamar N and Izopet J. Does chronic hepatitis E virus infection exist in immunocompetent patients? HEPATOLOGY 2015;61:427. C 2015 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27423 Potential conflict of interest: Nothing to report.
Effect of Interferon-Alpha Therapy on Hepatitis D Virus To the Editor: We read with interest the study by Guedj et al.1 describing the dynamics of hepatitis D virus (HDV) and hepatitis B surface antigen (HBsAg) after the commencement of pegylated interferon (IFN)-alpha 2a therapy. This study provides valuable data on this virus, which results in increased morbidity and mortality over hepatitis B virus (HBV) monoinfection. However, their conclusions on where IFN acts on the viral life cycle and their estimate of virion half-life are unlikely to be correct. Their calculations determined a median 8.5-day delay after IFN therapy started before HDV-RNA levels in serum decreased, yet they concluded that IFN impacted only on viral production, rather than new infection. This was less of a conclusion than an assumption given that their mathematical modeling excluded any inhibition of new infection (h 5 0 in their model). In contrast to the slow initial HDV-RNA delay observed in this study, HBV DNA decreases after a few hours with IFN and/or lamivudine therapy in HBV infection.2 Both of these drugs affect HBV virion production. Inhibition of virion production, as observed in the latter HBV study, will quickly affect viremia given that it acts closest to the stage that is renewing virus in serum. In contrast, inhibition of new infection will take a while to manifest itself on virion levels in serum given that a cell infected just before therapy will take some time to produce virus as the infection progresses through its complete replication cycle within that cell. This difference of effect determined by the length of the initial delay before viremia decreases has been observed in human immunodeficiency virus (HIV) by Murray et al.3 Monotherapy that inhibits fusion of a virion with a cell showed a larger initial delay in response than a drug that inhibited a later stage, such as integration of HIV DNA into the cell genome. All of these results and the long delay before HDV RNA
decreases after IFN suggest that this drug impacts on new infection, rather than the much later stage of HDV virion production. If that is correct, then the length of delay indicates that the intracellular infection cycle of HDV or of HBV is, on average, 8.5 days in vivo. It is difficult to be sure which virus life cycle is reflected by this delay because HDV can infect cells that are not already infected with HBV, but requires HBV infection to be able to produce new virus.4 This 8.5-day duration is consistent with a 7.9-day half-life estimate of HBV-infected cells.5 The very long 2.9-day half-life estimate for HDV virions is also unlikely to be correct. Prenylation inhibitor therapy, which acts at the HDV virion packaging stage within an infected cell, resulted in an 85% decrease of HDV RNA in serum of mice after 2 days,6 much faster than would be reflected by a 2.9-day half-life. ASHISH GOYAL, M.S. JOHN M. MURRAY, PH.D. School of Mathematics and Statistics University of New South Wales Sydney, New South Wales, Australia
References 1. Guedj J, Rotman Y, Cotler SJ, Koh C, Schmid P, Albrecht J, et al. Understanding early serum hepatitis D virus and HBsAg kinetics during pegylated interferon-alfa therapy via mathematical modeling. HEPATOLOGY 2014;60:1902-1910. 2. Sypsa VA, Mimidis K, Tassopoulos NC, Chrysagis D, Vassiliadis T, Moulakakis A, et al. A viral kinetic study using pegylated interferon alfa2b and/or lamivudine in patients with chronic hepatitis B/HBeAg negative. HEPATOLOGY 2005;42:77-85.
