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Occult hepatitis B virus infection in patients with chronic hepatitis C: A hidden threat
European Journal of Internal Medicine 22 (2011) e69–e70
Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Letter to the Editor Occult hepatitis B virus infection in patients with chronic hepatitis C: A hidden threat
To the Editor: On behalf of the author group, we would like to bring forward the following response on the letter to the editor commenting on our recent paper entitled “Role of occult hepatitis B virus in chronic hepatitis C patients with flare of liver enzymes” [1]. We appreciate the interest of Dr. Jazayeri and Dr. Alavian in our work. Dr. Jazayeri and Dr. Alavian raised a question about the high prevalence of occult HBV infection (OBI) reported in our work among chronic hepatitis C (CHC) patients with ALT flare. In their letter, they mentioned that the prevalence in our study was 82%. This number is not accurate; we detected occult HBV in 63.3% of patients with ALT flare. Since HBV and hepatitis C virus (HCV) share many of the same transmission routes, besides that our region suffers from high prevalence of unnecessary medical injections and transfusions, needlestick injuries and skin scarifications [2], therefore the high prevalence of occult HBV infection reported in CHC Egyptian patients is not surprising. Previous studies reported variable prevalence, ranging from 3% to 95% among different regions and demographics [3–5]. In addition, Kannangai et al. [6] reported that HBV genomes were detectable in 100% of injection drug users with CHC and ALT/AST flares. Second, they mentioned that other studies have shown no correlation between clinical outcomes and silent HBV infection and suggested liver biopsy for better assessment of liver damage than ALT flare. We totally agree, the clinical relevance of OBI on CHC remains controversial. Nevertheless, the impact of OBI on liver damage and clinical outcome was not our aim and was beyond the scope of this study. In addition, they inquired if hepatic flares in group two could be attributed only to the presence of HBV DNA. Certainly many factors can induce hepatic enzymes flare, in the design of our study; patients with conditions that may disturb ALT level were excluded. Our objective was simply to answer the following questions: Is it necessary to routinely check HBV DNA by a PCR-based assay in CHC patients? If not, when should this be considered? Our work showed that HBV DNA should be checked in CHC patients with ALT flare. Third, Dr. Jazayeri and Dr. Alavian pointed the importance of the suppressive effect of both viruses on each other. Several studies have shown that HBV and HCV interact with each other and affect immune responses [7]. It is generally accepted that superinfection with HCV might directly contribute to a certain proportion of cases with occult hepatitis B [8]. In cases of HBV carriers with HCV superinfection, HBeAg seroconversion and HBsAg clearance have been reported. HCV is capable of suppressing HBV replication, and this inhibitory effect is mediated by HCV core protein [9]. One study found that the inhibitory effect of HCV was genotype dependent [9], being more pronounced in genotype 1 HCV infections. Although HCV Genotyping was not performed in this study; it is well known that more than 90% of HCV infections in Egypt are due to
genotype 4 [10]. No data is available assessing the strength of the suppressive effect of HCV-4 on hepatitis B. Can HCV genotype 4 predominance in Egypt explain the high prevalence of OBI? More research is needed before reaching a firm conclusion on this aspect. Fourth, they suggested adding control group of CHC patients with positive HBsAg. This may give important information about the pattern of liver enzymes in CHC patients with OBI versus overt HBV co-infection. Similarly, adding group of non-viral chronic hepatitis with flares can help in comparing the prevalence of OBI in hepatitis C patients versus non-viral hepatitis. However, both intensions are irrelevant to the objectives of our study. As a final comment, Dr. Jazayeri and Dr. Alavian inquired about details for serology tests undertaken for the patients. They mentioned that two independent standard serologic tests should be performed before assigning the OBI. In our paper, we stated that patients were examined for HBsAg, anti-HBs, anti-HBc IgM, and anti-HBc IgG by ELISA technique using DIMA diagnostic kits, Germany. According to statements from the Taormina expert meeting on occult hepatitis B virus infection, the only serological test required for definition of OBI is negative hepatitis B surface antigen (HBsAg) “by currently available assays” [11]. Although the use of multivalent anti-HBs antibodies in the HBsAg assays is recommended for optimal detection of HBV variants with mutations in the S gene (escape mutants), diagnosis of OBI does not require a specific type of serological assay. Finally, we once again thank Dr. Jazayeri and Dr. Alavian for drawing an attention to the important aspects in our study. Their comments certainly brought up interesting questions that should be addressed in future studies and are of great relevance for better understanding of occult hepatitis B behavior. References
[1] Selim HS, Abou-Donia HA, Taha HA, El Azab GI, Bakry AF. Role of occult hepatitis B virus in chronic hepatitis C patients with flare of liver enzymes. Eur J Intern Med 2011;22:187–90. [2] Miller FD, Abu-Raddad LJ. Evidence of intense ongoing endemic transmission of hepatitis C virus in Egypt. Proc Natl Acad Sci USA 2010;107:14757–62. [3] Chu CJ, Lee SD. Occult hepatitis B virus infection in patients with chronic hepatitis C: an actor behind the scene or just a bystander? J Gastroenterol Hepatol 2010;25:221–3. [4] Saravanan S, Velu V, Nandakumar S, Madhavan V, Shanmugasundaram U, Murugavel KG, et al. Hepatitis B virus and hepatitis C virus dual infection among patients with chronic liver disease. J Microbiol Immunol Infect 2009;42:122–8. [5] Sagnelli E, Imparato M, Coppola N, Pisapia R, Sagnelli C, Messina V, et al. Diagnosis and clinical impact of occult hepatitis B infection in patients with biopsy proven chronic hepatitis C: a multicenter study. J Med Virol 2008;80: 1547–53. [6] Kannangai R, Vivekanandan P, Netski D, Mehta S, Kirk GD, Thomas DL, et al. Liver enzyme flares and occult hepatitis B in persons with chronic hepatitis C infection. J Clin Virol 2007;39:101–5. [7] Crockett SD, Keeffe EB. Natural history and treatment of hepatitis B virus and hepatitis C virus coinfection. Ann Clin Microbiol Antimicrob 2005;4:13. [8] Chu CJ, Lee SD. Hepatitis B virus/hepatitis C virus coinfection: epidemiology, clinical features, viral interactions and treatment. J Gastroenterol Hepatol 2008;23:512–20. [9] Schuttler CG, Fiedler N, Schmidt K, Repp R, Gerlich WH, Schaefer S. Suppression of hepatitis B virus enhancer 1 and 2 by hepatitis C virus core protein. J Hepatol 2002;37:855–62.
0953-6205/$ – see front matter © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2011.06.007
e70
Letter to the Editor
[10] Kamal SM, Nasser IA. Hepatitis C genotype 4: what we know and what we don't yet know. Hepatology 2008;47:1371–83. [11] Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol 2008;49:652–7.
Hossam A. Taha Gasser I. El Azab⁎ Hepatology Department, National Liver Institute, Menoufiya University, Egypt *Corresponding author at: Hepatology Department, National Liver Institute, Menoufiya University, Sheben Al koom, National Liver Institute: 32111, Egypt. Tel.: + 20 180250026. E-mail address: [email protected] (G. I. El Azab). 28 May 2011
Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Letter to the Editor Occult hepatitis B virus infection in patients with chronic hepatitis C: A hidden threat
To the Editor: On behalf of the author group, we would like to bring forward the following response on the letter to the editor commenting on our recent paper entitled “Role of occult hepatitis B virus in chronic hepatitis C patients with flare of liver enzymes” [1]. We appreciate the interest of Dr. Jazayeri and Dr. Alavian in our work. Dr. Jazayeri and Dr. Alavian raised a question about the high prevalence of occult HBV infection (OBI) reported in our work among chronic hepatitis C (CHC) patients with ALT flare. In their letter, they mentioned that the prevalence in our study was 82%. This number is not accurate; we detected occult HBV in 63.3% of patients with ALT flare. Since HBV and hepatitis C virus (HCV) share many of the same transmission routes, besides that our region suffers from high prevalence of unnecessary medical injections and transfusions, needlestick injuries and skin scarifications [2], therefore the high prevalence of occult HBV infection reported in CHC Egyptian patients is not surprising. Previous studies reported variable prevalence, ranging from 3% to 95% among different regions and demographics [3–5]. In addition, Kannangai et al. [6] reported that HBV genomes were detectable in 100% of injection drug users with CHC and ALT/AST flares. Second, they mentioned that other studies have shown no correlation between clinical outcomes and silent HBV infection and suggested liver biopsy for better assessment of liver damage than ALT flare. We totally agree, the clinical relevance of OBI on CHC remains controversial. Nevertheless, the impact of OBI on liver damage and clinical outcome was not our aim and was beyond the scope of this study. In addition, they inquired if hepatic flares in group two could be attributed only to the presence of HBV DNA. Certainly many factors can induce hepatic enzymes flare, in the design of our study; patients with conditions that may disturb ALT level were excluded. Our objective was simply to answer the following questions: Is it necessary to routinely check HBV DNA by a PCR-based assay in CHC patients? If not, when should this be considered? Our work showed that HBV DNA should be checked in CHC patients with ALT flare. Third, Dr. Jazayeri and Dr. Alavian pointed the importance of the suppressive effect of both viruses on each other. Several studies have shown that HBV and HCV interact with each other and affect immune responses [7]. It is generally accepted that superinfection with HCV might directly contribute to a certain proportion of cases with occult hepatitis B [8]. In cases of HBV carriers with HCV superinfection, HBeAg seroconversion and HBsAg clearance have been reported. HCV is capable of suppressing HBV replication, and this inhibitory effect is mediated by HCV core protein [9]. One study found that the inhibitory effect of HCV was genotype dependent [9], being more pronounced in genotype 1 HCV infections. Although HCV Genotyping was not performed in this study; it is well known that more than 90% of HCV infections in Egypt are due to
genotype 4 [10]. No data is available assessing the strength of the suppressive effect of HCV-4 on hepatitis B. Can HCV genotype 4 predominance in Egypt explain the high prevalence of OBI? More research is needed before reaching a firm conclusion on this aspect. Fourth, they suggested adding control group of CHC patients with positive HBsAg. This may give important information about the pattern of liver enzymes in CHC patients with OBI versus overt HBV co-infection. Similarly, adding group of non-viral chronic hepatitis with flares can help in comparing the prevalence of OBI in hepatitis C patients versus non-viral hepatitis. However, both intensions are irrelevant to the objectives of our study. As a final comment, Dr. Jazayeri and Dr. Alavian inquired about details for serology tests undertaken for the patients. They mentioned that two independent standard serologic tests should be performed before assigning the OBI. In our paper, we stated that patients were examined for HBsAg, anti-HBs, anti-HBc IgM, and anti-HBc IgG by ELISA technique using DIMA diagnostic kits, Germany. According to statements from the Taormina expert meeting on occult hepatitis B virus infection, the only serological test required for definition of OBI is negative hepatitis B surface antigen (HBsAg) “by currently available assays” [11]. Although the use of multivalent anti-HBs antibodies in the HBsAg assays is recommended for optimal detection of HBV variants with mutations in the S gene (escape mutants), diagnosis of OBI does not require a specific type of serological assay. Finally, we once again thank Dr. Jazayeri and Dr. Alavian for drawing an attention to the important aspects in our study. Their comments certainly brought up interesting questions that should be addressed in future studies and are of great relevance for better understanding of occult hepatitis B behavior. References
[1] Selim HS, Abou-Donia HA, Taha HA, El Azab GI, Bakry AF. Role of occult hepatitis B virus in chronic hepatitis C patients with flare of liver enzymes. Eur J Intern Med 2011;22:187–90. [2] Miller FD, Abu-Raddad LJ. Evidence of intense ongoing endemic transmission of hepatitis C virus in Egypt. Proc Natl Acad Sci USA 2010;107:14757–62. [3] Chu CJ, Lee SD. Occult hepatitis B virus infection in patients with chronic hepatitis C: an actor behind the scene or just a bystander? J Gastroenterol Hepatol 2010;25:221–3. [4] Saravanan S, Velu V, Nandakumar S, Madhavan V, Shanmugasundaram U, Murugavel KG, et al. Hepatitis B virus and hepatitis C virus dual infection among patients with chronic liver disease. J Microbiol Immunol Infect 2009;42:122–8. [5] Sagnelli E, Imparato M, Coppola N, Pisapia R, Sagnelli C, Messina V, et al. Diagnosis and clinical impact of occult hepatitis B infection in patients with biopsy proven chronic hepatitis C: a multicenter study. J Med Virol 2008;80: 1547–53. [6] Kannangai R, Vivekanandan P, Netski D, Mehta S, Kirk GD, Thomas DL, et al. Liver enzyme flares and occult hepatitis B in persons with chronic hepatitis C infection. J Clin Virol 2007;39:101–5. [7] Crockett SD, Keeffe EB. Natural history and treatment of hepatitis B virus and hepatitis C virus coinfection. Ann Clin Microbiol Antimicrob 2005;4:13. [8] Chu CJ, Lee SD. Hepatitis B virus/hepatitis C virus coinfection: epidemiology, clinical features, viral interactions and treatment. J Gastroenterol Hepatol 2008;23:512–20. [9] Schuttler CG, Fiedler N, Schmidt K, Repp R, Gerlich WH, Schaefer S. Suppression of hepatitis B virus enhancer 1 and 2 by hepatitis C virus core protein. J Hepatol 2002;37:855–62.
0953-6205/$ – see front matter © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2011.06.007
e70
Letter to the Editor
[10] Kamal SM, Nasser IA. Hepatitis C genotype 4: what we know and what we don't yet know. Hepatology 2008;47:1371–83. [11] Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol 2008;49:652–7.
Hossam A. Taha Gasser I. El Azab⁎ Hepatology Department, National Liver Institute, Menoufiya University, Egypt *Corresponding author at: Hepatology Department, National Liver Institute, Menoufiya University, Sheben Al koom, National Liver Institute: 32111, Egypt. Tel.: + 20 180250026. E-mail address: [email protected] (G. I. El Azab). 28 May 2011