|Year : 2016 | Volume
| Issue : 4 | Page : 149-152
Impact of dual hepatitis B and C infection on disease severity and treatment outcome: updated review
Gamal Esmat, Tamer Elbaz
Department of Endemic Hepatogastroenterology, Faculty of Medicine, Cairo University, Giza, Egypt
|Date of Submission||09-Feb-2016|
|Date of Acceptance||04-Jul-2016|
|Date of Web Publication||23-Jun-2017|
Associate Professor Endemic Hepatogastroenterology, Endemic Hepatogastroenterology Department, Faculty of Medicine, Cairo University
Source of Support: None, Conflict of Interest: None
Hepatitis B, C are commonly present together. They both share same routes of transmission. Dual infection carries a wide, variable range of virological, clinical profiles. Even in terms of management, large debates arose due to related issues such as priority for treatment, fate of the second virus if the primary one is eradicated.
Keywords: hepatitis B, hepatitis C, dual, dual infection
|How to cite this article:|
Esmat G, Elbaz T. Impact of dual hepatitis B and C infection on disease severity and treatment outcome: updated review. Al-Azhar Assiut Med J 2016;14:149-52
|How to cite this URL:|
Esmat G, Elbaz T. Impact of dual hepatitis B and C infection on disease severity and treatment outcome: updated review. Al-Azhar Assiut Med J [serial online] 2016 [cited 2018 Mar 22];14:149-52. Available from: http://www.azmj.eg.net/text.asp?2016/14/4/149/208929
| Introduction|| |
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are two hepatotropic viruses that cause chronic liver diseases and consequent serious sequelae. In high endemic areas and among people with a high risk for parenteral infections, combined infection with both viruses is frequent and not uncommon . High-risk populations include intravenous drug users (IDUs), patients undergoing regular hemodialysis, and recipients of organ transplantations .
| Epidemiology|| |
The WHO announced that more than 500 million individuals are chronically infected with HBV or HCV worldwide . Chronic HCV patients of 2–10% are positive for hepatitis B surface antigen (HBsAg) and 5–7% of HBV patients are positive for HCV antibody (HCV-Ab) ,. In other words, it is estimated that dual infection is present in 3.5–7 million individuals (among 350 million HBV carriers). True incidence may be higher if occult HBV infection is taken into consideration .
In the USA, Tyson et al.  conducted a large cohort study and found a prevalence of 1.4% for overt HBV infection in HCV-positive patients, and one-third of the study population showed positivity for antibodies directed to HBV antigens. In Egypt, a study found that occult HBV infection occurred in 3.9% of chronic HCV genotype four patients and tended to be associated with higher baseline HCV viral load as well as younger age patients and less hepatic fibrosis .
Focused on certain high-risk groups, eligible reports detected a high prevalence of HCV-Ab among IDUs that can reach even more than 80%. An estimate of 10 million IDUs could be positive for HCV-Ab. As regards HBsAg, reports estimated an incidence ranging from 5 to 10% in certain countries and more than 10% in others with an estimate of 6.4 and 1.2 million IDUs being positive for anti-HB core and HBsAg, respectively .
| Virological and clinical spectra of dual infection|| |
In clinical practice, coinfection with both viruses is usually identified by the seropositivity for HBsAg and HCV-Ab. Consequent detection of viral genomes (essentially HCV RNA) is important to confirm the current status of coinfection. In cases of acute hepatitis, three different scenarios are proposed: (a) first time exposure to both viruses simultaneously; (b) HCV superinfection for a chronic HBsAg carrier patient; and (c) HBV superinfection for a chronic HCV-positive patient. In these three situations, all subsequent outcomes can occur from complete recovery from one or both viruses up to fulminant liver cell failure and death .
Another clinical form is coinfection of HCV with occult HBV. Occult HBV is the presence of HBV DNA in HBsAg-negative individuals and could be either seronegative or seropositive for anti-HBc IgG with a higher predominance of seropositivity. It may need intrahepatic assessment of HBV DNA . Impact of occult HBV on HCV infection is highly variable .
As both infections are rather acquired through blood and blood products, this dual infection can be triple if associated with hepatitis D virus or HIV . Quadruple infection is also possible (HBV, HCV, hepatitis D virus, and HIV) ,,.
An extremely wide and different spectrum of virological profiles can be detected and were previously documented in cases of dual HBV and HCV infections . Early in-vitro studies declared that HCV core protein strongly inhibits the replication of HBV ,. As HCV generally suppresses HBV, studies found hepatitis B e antigen seroconversion as well as HBsAg seroclearance in chronic HBV patients who were superinfected with HCV ,.
However, other studies reported that HCV RNA levels significantly decreased in some dually infected patients when HBV DNA in serum was detected compared with PCR-negative patients for HBV . A dominant effect of HBV even led to higher rates of HCV RNA clearance . Recent in-vitro studies used full-length HBV genomes and HCV replicons detected possible dual replications of both viruses in same hepatocytes without any evidence of overt interference, either in cases of simultaneous coinfection or superinfection ,. Specific inhibition of one virus has not led to affection of replication or gene expression of second virus . From previous evidence of extremely variable virological profiles, it is truly possible that dominance of one of the two viruses may alternate and change at different periods during the infection. Even more, suppression of the dominant virus can lead to reactivation of the other virus .
In terms of clinical outcomes of dual infection, studies were similarly debatable. Many studies studied the increased severity of liver disease compared with infection by a single virus. A higher prevalence of liver cirrhosis and hepatic decompensation dominated in dual rather than monoinfection ,,,,,,,. A study found increased prevalence of HCV-Ab with severity of chronic HBV infection. HCV-Ab was detected in 8% of chronic HBV infection; it was detected in 10 and 17% of patients who suffered from HBV-related cirrhosis and HBV-related hepatocellular carcinoma (HCC), respectively . Studies also reported that serum alanine aminotransferase and histological activity as well as liver cirrhosis were more common in chronic HCV patients associated with occult HBV infection with a documented synergistic action of both viruses together in progression of liver disease ,,.
In contrast, Sagnelli et al.  reported the absence of association between occult HBV and degree of liver necro inflammation and fibrosis in chronic HCV patients. Similar conclusions were similarly reported by other studies ,,,,,.
Different studies debated the issue of impact of dual infection on the development of HCC. The Hepatitis Antiviral Long-Term Treatment against Cirrhosis (HALT-C) prospective trial followed up chronic HCV patients and advanced liver fibrosis patients for different clinical outcomes. They found no significant difference in the prevalence of serum anti-HBcore or HBV DNA between patients who developed HCC and those who did not develop it. They highlighted that neither previous nor occult HBV infection is related to HCC development among chronic advanced HCV patients . In contrast, another study evaluated the development of HCC in patients who suffered from dual infection versus patients who suffered from HBV or HCV monoinfection. HCC was more frequently documented in dually infected patients (14%) as compared with 2 and 4% of patients who developed malignancy on top of chronic HBV and HCV infections, respectively . A meta-analysis study reported a statistically significantly higher relative risk for HCC in cases of dual infections [odds ratio (OR)=165] compared with HBV (OR=22.5) and HCV (OR=17.3) monoinfected patients. Moreover, another study found that some dually infected patients still develop HCC after achieving HCV-sustained virologic response (SVR) and even HBsAg seroclearance after treatment .
Another form of clinical interference is the impact of chronic HCV infection on response to HBV vaccination. Generally, studies declared a poor response rate to vaccination in HCV-infected patients compared with normal healthy individuals and those who were spontaneously resolved from HCV infection ,,.
Finally, it looks that single-point evaluation of viral genomes of both viruses does not provide a reliable and definite conclusion about the impact of each virus. As such, repeated evaluation is necessary for proper assessment before specific treatments, during their therapies, and thereafter follow-up after treatments ,.
| Treatment response|| |
Treatment of dual infection is a real challenge. Many studies tried to answer many pending questions such as priority of treatment and fate of second virus after treatment of the primary one.
Treatment priority can be addressed through determination of the relative viral activity of both hepatitis viruses. In addition, response to antiviral therapy is an important factor. Active hepatitis C can be successfully managed and is documented as the dominant affecting virus in 70% of dually infected patients . This is the reason for the priority to treat HCV in the majority of cases.
Several studies reported a good response rate of HCV in dually infected patients that was comparable to rates in monoinfected patients treated for HCV. A large multicenteric study that was conducted in Taiwan documented 72.2% SVR in dually infected patients with genotype 1 HCV versus 77.3% in monoinfected HCV patients. Moreover, they reported 82.8% SVR in genotypes 2/3 infections versus 84%. They used pegylated interferon and ribavirin . Similar findings were reported when treating HCV in occult HBV-infected patients ,,,, whereas some studies reported contradictory results ,,. This difference in findings may be attributed to the type of treatment, different protocols, HBV status, and types of HCV genotypes treated.
Fate of HBV in dually infected patients who are successfully managed for HCV is an important concern. Reactivation of HBV and its replication is a common observation ,,. However, a study reported HBV virologic response with same HCV treatment using pegylated interferon-based therapy in 56% of dually infected patients. HBsAg clearance was seen in 11.2% of patients, whereas other patients suffered from reappearance of HBV DNA and elevation of ALT levels . However, certain studies concluded a maintenance of HBV status independent of HCV response to treatment ,.
| Conclusion|| |
Dual infection carries many debatable issues either in virological and clinical patterns, treatment responsiveness or prioritization to treatment. Mostly, the behavior of each virus looks to be independent with somewhat points of interactions. Serial evaluation at different times for the virological status of both viruses is crucial.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Tyson GL, Kramer JR, Duan Z, Davila JA, Richardson PA, El-Serag HB. Prevalence and predictors of hepatitis B virus coinfection in a United States cohort of hepatitis C virus-infected patients. Hepatology 2013;58:538–545.
Chu CJ, Lee SD. Hepatitis B virus/hepatitis C virus coinfection: epidemiology, clinical features, viral interactions and treatment. J Gastroenterol Hepatol 2008;23:512–520.
Caccamo G, Saffioti F, Raimondo G. Hepatitis B virus and hepatitis C virus dual infection. World J Gastroenterol 2014;20:14559–14567.
Peters MG. Special populations with hepatitis B virus infection. Hepatology 2009;49(Suppl):S146–S155.
Liu CJ, Chen PJ, Chen DS. Dual chronic hepatitis B virus and hepatitis C virus infection. Hepatol Int 2009;3:517–525.
Nelson PK, Mathers BM, Cowie B, Hagan H, Des Jarlais D, Horyniak D, Degenhardt L. Global epidemiology of hepatitis B and hepatitis C in people who inject drugs: results of systematic reviews. Lancet 2011;378:571–583.
Emara MH, El-Gammal NE, Mohamed LA, Bahgat MM. Occult hepatitis B infection in Egyptian chronic hepatitis C patients: prevalence, impact on pegylated interferon/ribavirin therapy. Virol J 2010;7:324.
Jang JY, Jeong SW, Cheon SR, Lee SH, Kim SG, Cheon YK et al.
Clinical significance of occult hepatitis B virus infection in chronic hepatitis C patients. Korean J Hepatol 2011;17:206–212.
Fernandez-Rodriguez CM, Gutierrez ML, Lledó JL, Casas ML. Influence of occult hepatitis B virus infection in chronic hepatitis C outcomes. World J Gastroenterol 2011;17:1558–1562.
Riaz M, Idrees M, Kanwal H, Kabir F. An overview of triple infection with hepatitis B, C and D viruses. Virol J 2011;8:368.
Deterding K, Pothakamuri SV, Schlaphoff V, Hadem J, Metzler F, Bahr MJ et al.
Clearance of chronic HCV infection during acute delta hepatitis. Infection 2009;37:159–162.
Bhasin D, Zhang X, Ward SC, Chang CY. A case of quadruple viral infections and elevated aminotransferase activities. Semin Liver Dis 2012;32:262–266.
Maida I, Ríos MJ, Pérez-Saleme L, Ramos B, Soriano V, Pegram PS et al.
Profile of patients triply infected with HIV and the hepatitis B and C viruses in the HAART era. AIDS Res Hum Retroviruses 2008;24:679–683.
Raimondo G, Brunetto MR, Pontisso P, Smedile A, Maina AM, Saitta C et al.
Longitudinal evaluation reveals a complex spectrum of virological profiles in hepatitis B virus/hepatitis C virus-coinfected patients. Hepatology 2006;43:100–107.
Shih CM, Lo SJ, Miyamura T, Chen SY, Lee YH. Suppression of hepatitis B virus expression and replication by hepatitis C virus core protein in HuH-7 cells. J Virol 1993;67:5823–5832.
Schüttler 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;37:855–862.
Liaw YF, Chen YC, Sheen IS, Chien RN, Yeh CT, Chu CM. Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology 2004;126:1024–1029.
Liaw YF, Lin SM, Sheen IS, Chu CM. Acute hepatitis C virus superinfection followed by spontaneous HBeAg seroconversion and HBsAg elimination. Infection 1991;19:250–251.
Zarski JP, Bohn B, Bastie A, Pawlotsky JM, Baud M, Bost-Bezeaux F et al.
Characteristic of patients with dual infection by hepatitis B and C viruses. J Hepatol 1998;28:27–33.
Pontisso P, Gerotto M, Ruvoletto MG, Fattovich G, Chemello L, Tisminetzky S et al.
Hepatitis C genotypes in patients with dual hepatitis B and C virus infection. J Med Virol 1996;48:157–160.
Eyre NS, Phillips RJ, Bowden S, Yip E, Dewar B, Locarnini SA, Beard MR. Hepatitis B virus and hepatitis C virus interaction in Huh-7 cells. J Hepatol 2009;51:446–457.
Bellecave P, Gouttenoire J, Gajer M, Brass V, Koutsoudakis G, Blum HE et al.
Hepatitis B and C virus coinfection: a novel model system reveals the absence of direct viral interference. Hepatology 2009;50:46–55.
Liu JY, Sheng YJ, Hu HD, Zhong Q, Wang J, Tong SW et al.
The influence of hepatitis B virus on antiviral treatment with interferon and ribavirin in Asian patients with hepatitis C virus/hepatitis B virus coinfection: a meta-analysis. Virol J 2012;9:186.
Mohamed AS, Karawi MA, Mesa GA. et al.
.. Dual infection with hepatitis C and B viruses: clinical and histological study in Saudi patients. Hepatogastroenterology 1997;44:1404–1406.
Fong TL, di Bisceglie AM, Waggoner JG, Banks SM, Hoofnagle JH. The significance of antibody to hepatitis C virus in patients with chronic hepatitis B. Hepatology. 1991;14:64–67.
Liu CJ, Chuang WL, Lee CM, Yu ML, Lu SN, Wu SS et al.
Peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses. Gastroenterology. 2009;136:496–504.
Lee LP, Dai CY, Chuang WL, Chang WY, Hou NJ, Hsieh MY et al.
Comparison of liver histopathology between chronic hepatitis C patients and chronic hepatitis B and C-coinfected patients. J Gastroenterol Hepatol 2007;22:515–517.
Liu CJ, Liou JM, Chen DS, Chen PJ. Natural course and treatment of dual hepatitis B virus and hepatitis C virus infections. J Formos Med Assoc 2005;104:783–791.
Sagnelli E, Coppola N, Messina V, di Caprio D, Marrocco C, Marotta A et al.
HBV superinfection in hepatitis C virus chronic carriers, viral interaction, and clinical course. Hepatology 2002;36:1285–1291.
Chen DS, Kuo GC, Sung JL, Lai MY, Sheu JC, Chen PJ et al.
Hepatitis C virus infection in an area hyperendemic for hepatitis B and chronic liver disease: the Taiwan experience. J Infect Dis 1990;162:817–822.
Sagnelli E, Coppola N, Scolastico C, Mogavero AR, Filippini P, Piccinino F. HCV genotype and ‘silent’ HBV coinfection: two main risk factors for a more severe liver disease. J Med Virol 2001;64:350–355.
Fukuda R, Ishimura N, Niigaki M, Hamamoto S, Satoh S, Tanaka S et al.
Serologically silent hepatitis B virus coinfection in patients with hepatitis C virus-associated chronic liver disease: clinical and virological significance. J Med Virol 1999;58:201–207.
Uchida T, Kaneita Y, Gotoh K, Kanagawa H, Kouyama H, Kawanishi T, Mima S Hepatitis C virus is frequently coinfected with serum marker-negative hepatitis B virus: probable replication promotion of the former by the latter as demonstrated by in vitro cotransfection. J Med Virol 1997;52:399–405.
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;80:1547–1553.
Fabris P, Brown D, Tositti G, Bozzola L, Giordani MT, Bevilacqua P et al.
Occult hepatitis B virus infection does not affect liver histology or response to therapy with interferon alpha and ribavirin in intravenous drug users with chronic hepatitis C. J Clin Virol 2004;29:160–166.
Hui CK, Lau E, Wu H, Monto A, Kim M, Luk JM et al.
Fibrosis progression in chronic hepatitis C patients with occult hepatitis B co-infection. J Clin Virol 2006;35:185–192.
Nirei K, Kaneko M, Moriyama M, Arakawa Y. The clinical features of chronic hepatitis C are not affected by the coexistence of hepatitis B virus DNA in patients negative for hepatitis B surface antigen. Intervirology 2000;43:95–101.
Matsuoka S, Nirei K, Tamura A, Nakamura H, Matsumura H, Oshiro S et al.
Influence of occult hepatitis B virus coinfection on the incidence of fibrosis and hepatocellular carcinoma in chronic hepatitis C. Intervirology 2008;51:352–361.
Kazemi-Shirazi L, Petermann D, Müller C. Hepatitis B virus DNA in sera and liver tissue of HBsAg negative patients with chronic hepatitis C. J Hepatol 2000;33:785–790.
Lok A, Everhart J, Di Bisceglie A, Kim H-Y., Hussain M, Morgan THALT-C Trial Group. Occult and previous hepatitis B virus infection are not associated with hepatocellular carcinoma in US patients with chronic hepatitis C. Hepatology 2011;54:434–442.
Zampino R, Pisaturo MA, Cirillo G, Marrone A, Macera M, Rinaldi L et al.
Hepatocellular carcinoma in chronic HBV-HCV co-infection is correlated to fibrosis and disease duration. Ann Hepatol 2015;14:75–82.
Liu CJ, Chen PJ. Updates on the treatment and outcomes of dual chronic hepatitis C and B virus infection. World J Gastroenterol 2014;20:2955–2961.
Elefsiniotis IS, Vezali E, Kamposioras K, Pantazis KD, Tontorova R, Ketikoglou I et al.
Immunogenicity of recombinant hepatitis B vaccine in treatment-naive and treatment-experienced chronic hepatitis C patients: the effect of pegylated interferon plus ribavirin treatment. World J Gastroenterol 2006;12:4420–4424.
Daryani NE, Nassiri-Toosi M, Rashidi A, Khodarahmi I. Immunogenicity of recombinant hepatitis B virus vaccine in patients with and without chronic hepatitis C virus infection: a case-control study. World J Gastroenterol 2007;13:294–298.
Moorman JP, Zhang CL, Ni L, Ma CJ, Zhang Y, Wu XY et al.
Impaired hepatitis B vaccine responses during chronic hepatitis C infection: involvement of the PD-1 pathway in regulating CD4(+) T cell responses. Vaccine 2011;29:3169–3176.
Raimondo G, Saitta C. Treatment of the hepatitis B virus and hepatitis C virus co-infection: still a challenge for the hepatologist. J Hepatol 2008;49:677–679.
Hasegawa I, Orito E, Tanaka Y, Hirashima N, Sakakibara K, Sakurai M et al.
Impact of occult hepatitis B virus infection on efficacy and prognosis of interferon-alpha therapy for patients with chronic hepatitis C. Liver Int 2005;25:247–253.
Levast M, Larrat S, Thelu MA, Nicod S, Plages A, Cheveau A et al.
Prevalence and impact of occult hepatitis B infection in chronic hepatitis C patients treated with pegylated interferon and ribavirin. J Med Virol 2010;82:747–754.
Mrani S, Chemin I, Menouar K, Guillaud O, Pradat P, Borghi G et al.
Occult HBV infection may represent a major risk factor of non-response to antiviral therapy of chronic hepatitis C. J Med Virol 2007;79:1075–1081.
Cacciola I, Pollicino T, Squadrito G, Cerenzia G, Orlando ME, Raimondo G. Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease. N Engl J Med 1999;341:22–26.
De Maria N, Colantoni A, Friedlander L, Leandro G, Idilman R, Harig J, van Thiel DH. The impact of previous HBV infection on the course of chronic hepatitis C. Am J Gastroenterol 2000;95:3529–3536.
Zignego A, Fontana R, Puliti S, Monti M, Careccia G, Giannelli F et al.
Impaired response to alpha interferon in patients with an inapparent hepatitis B and hepatitis C virus coinfection. Arch Virol 1997;142:535–544.
Kim YJ, Lee JW, Kim YS, Jeong SH, Kim YS, Yim HJ et al.
Clinical features and treatment efficacy of peginterferonalfa plus ribavirin in chronic hepatitis C patients coinfected with hepatitis B virus. Korean J Hepatol 2011;17:199–205.
Yu JW, Sun LJ, Zhao YH, Kang P, Gao J, Li SC. Analysis of the efficacy of treatment with peginterferon alpha-2a and ribavirin in patients coinfected with hepatitis B virus and hepatitis C virus. Liver Int 2009;29:1485–1493.
Gordon SC, Sherman KE. Treatment of HBV/HCV coinfection: releasing the enemy within. Gastroenterology 2009;136:393–396.
Saitta C, Pontisso P, Brunetto MR, Fargion S, Gaeta GB, Niro GA et al.
Virological profiles in hepatitis B virus/hepatitis C virus coinfected patients under interferon plus ribavirin therapy. Antivir Ther 2006;11:931–934.