World J Gastroenterol. 2011 March 28; 17(12): 1538-1542.
Published online 2011 March 28. doi: 10.3748/wjg.v17.i12. 1538.
©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
Prevalence of occult hepatitis B virus infection
Maria Luisa Gutiérrez-García, Conrado M Fernandez-Rodriguez, Jose Luis Lledo-Navarro, Ingrid Buhigas-Garcia, Service of Gastroenterology, Hospital Universitario Fundación Alcorcón, Av Budapest-1, 28922 Alcorcón, Madrid, Spain
Received August 6, 2010; Revised November 16, 2010; Accepted November 23, 2010;
Occult hepatitis B virus (HBV) infection (OBI) is characterized by the persistence of HBV DNA in the liver tissue in individuals negative for the HBV surface antigen. The prevalence of OBI is quite variable depending on the level of endemic disease in different parts of the world, the different assays utilized in the studies, and the different populations studied. Many studies have been carried out on OBI prevalence in different areas of the world and categories of individuals. The studies show that OBI prevalence seems to be higher among subjects at high risk for HBV infection and with liver disease than among individuals at low risk of infection and without liver disease.
Keywords: Occult hepatitis B virus infection, Hepatitis B virus DNA, Anti-HBc, Hepatitis B virus seronegative, Hepatitis C, Crytogenetic hepatitis, Dialysis, Human immunodeficiency virus, Blood donors
Chronic hepatitis B virus (HBV) infection is characterised by persistence of HBV surface antigen (HBsAg) and presence of HBV DNA in serum.
Occult HBV infection (OBI) is the persistence of viral genoma in the liver tissue in individuals negative for HBsAg. OBI is defined by the presence of HBV DNA in the liver (with detectable or undetectable HBV DNA in the serum) in patients with serological markers of previous infection (anti-HBc and/or anti-HBs positive) or in patients without serological markers (anti-HBc and/or anti-HBs negative). The prevalence of OBI is quite variable depending on the level of endemic disease in different parts of the world, the different assays utilized in the studies, and the different populations studied[1
]. The populations in which prevalence of OBI has been investigated are: patients with liver disease (HCV infected patients and patients with cryptogenetic liver diseases), patients at high risk of parenteral-transmitted infection (intravenous drug addicts, hemophiliacs), patients on hemodialysis, human immunodeficiency virus (HIV) infected patients and apparently healthy individuals (blood donors, general population)[1
]. The purpose of this review is to provide comprehensive information on overall OBI prevalence as well as in patients with different chronic liver diseases.
HCV INFECTED PATIENTS
As HBV and HCV share many of the same transmission routes, and infection with both viruses is common, the high prevalence of OBI in patients with hepatitis C is not unexpected. HCV infected patients have the highest prevalence of OBI[2,3
]. Cacciola et al[2
] published the first study of prevalence of OBI in patients with chronic hepatitis C; in this study HBV sequences were found in liver tissue from 66 of the 200 (33%) HCV infected patients and in 7 of the 50 (14%) HCV negative patients, 46 of the 66 patients were anti-HBc positive and 20 of the 66 were anti-HBc negative. They also found very low levels of viremia and the prevalence of OBI was particularly high among patients with anti-HBV antibodies although OBI was also detected in patients who were negative for all HBV serum markers[2
]. The study of Cacciola et al[2
] also demonstrated that OBI was significantly correlated with cirrhosis among HCV infected patients; 22 of the 66 patients (33%) with HCV infection and OBI had cirrhosis as compared with 26 of the 134 (19%) with HCV infection and no OBI, suggesting that OBI can accelerate the evolution to cirrhosis in HCV infected patients. Bréchot et al[4
] reviewed all the studies published in anti-VHC patients using PCR on serum and liver and the conclusion was that about 20%-30% and 40%-50% of serum and livers respectively showed HBV DNA positivity.
CRYPTOGENETIC LIVER DISEASE
In patients with cryptogenetic liver disease there is less available information than in HCV patients but the prevalence is thought to range from 19% to 31%[5,6
]. Chemin et al[6
] studied 50 patients with chronic hepatitis non-A non-E and reported a high prevalence of low-grade HBV infection. HBV DNA was detected by PCR in serum in a high proportion of cases (15/50; 30%); in all cases HBV DNA detection in serum was further confirmed on liver biopsies. 11 of the 15 (73%) patients who were HBV DNA positive were found to be anti-HBc positive, and all the patients had 104
or less HBV DNA copies per mL. Among the positive HBV DNA patients 8/15 (53%) had severe fibrosis and cirrhosis and none of the patients had steatosis, so low-grade HBV infection was associated with more severe liver disease. The histopathological follow-up showed that some patients progressed to cirrhosis[5
]. Berasain et al[5
] investigated 1075 patients with chronic liver disease and in 109 (10%) the aetiology could not be defined by clinical, biochemical and serological data. In these cases liver biopsy was reviewed, then the histopathological findings and implication of hepatitis viruses B and C was investigated in crytogenetic liver disease. HBV DNA and HCV RNA were determined in serum by PCR. HBV DNA and HCV RNA were detected in the serum of 18% and 8% patients with cryptogenetic and noncryptogenic liver diseases respectively. Liver biopsies showed non specific changes or non-alcoholic steatohepatitis (NASH) in 48% and chronic hepatitis or cirrhosis in 52%. The proportion of cases with detectable HBV DNA or HCV RNA was 14% in the first group, 30% in the group with chronic hepatitis and 61% in the group with cirrhosis, so occult viral infection was found in a high proportion of patients with chronic hepatitis or cirrhosis and in a low percentage of patients with NASH or non-specific changes. Two patients with cryptogentic cirrhosis underwent liver transplantation, and in these 2 cases HBV DNA was detected in the explanted liver[6
Hemodialysis patients are at high risk of acquiring parenterally transmitted infections, not only because of the large number of received blood transfusions, and the invasive procedures that they undergo, but also because of their immunosuppressed state. Several reports have been published about prevalence in haemodialysis patients ranging from 0% to 36%. Most of these studies show that OBI is usually associated with low levels of HBV and have investigated the presence of of OBI in the context of chronic HCV infection[7-13
]. These studies demonstrated HBV DNA by PCR in serum samples; there were no studies demonstrating HBV DNA in liver extracts because of the lack of available liver tissue in the setting of haemodialysis. The studies of Fabrizi et al[9
] and Minuk et al[10
] show that conventional serological features of HBV DNA positive subjects do not distinguish these individuals from the remainder of the dialysis patient population; therefore, routine serological testing is not able to identify the occult infection in this population. Several studies have demonstrated that the prevalence of OBI is not associated with the presence of anti-VHC antibodies in hemodialysis patients[14-16
]. Recently, one study has shown an OBI prevalence of 9.8% in continuous ambulatory peritoneal dialysis (CPAP)[17
HIV INFECTED PATIENTS
OBI in HIV infected patients may be viewed as the result of opportunistic reactivation of HBV due to cellular immune deficiency, as reflected by the decreased CD4 counts in HIV infection. The prevalence of OBI in HIV infected patients remains controversial and the available data are widely divergent. Published studies report a prevalence between 0% to 89%[18-26
]. The cause of these variations is the same as in HIV-negative patients: level of endemic disease in differences parts of the world, the different assays utilized in the studies, and the different populations studied. HIV patients with OBI have significantly lower CD4 counts and high plasma HIV RNA loads[20,27
]. The risk factors, the clinical significance and the effect of highly active antiretroviral therapy (HAART) are unknown. Recently, Cohen Stuart et al[28
] analyzed the prevalence of OBI in 191 HIV and anti-HBc positive before HAART and also during the immune reconstitution phase that follows initiation of HAART. Anti-HBs was positive in 128/191 (67%), and negative in 45/191 (24%). Plasma HBV DNA was detected in 9/191 corresponding to a prevalence of 4.7%. In the isolated anti-HBc group the prevalence was 11.1%, whereas in those anti-HBs positive the prevalence was 3.1%; this difference was not significant. The study demonstrated the absence of hepatic flares after start of HAART and showed that HBV DNA remained undetectable in all patients after starting HAART. Therefore OBI has no clinical impact when immune reconstitution is achieved with HAART containing at least one HBV inhibiting compound.
Despite continuous technical improvement in blood donation screening, hepatitis B infection remains a major risk of transfusion-transmitted viral infection. Reduction of HBV residual risk is achieved by developing more sensitive HBsAg tests, by adopting anti-HBc screening if appropriate and implementing HBV nucleic acid test (NAT).
The prevalence of OBI among HBsAg negative blood donors is quite variable depending on the level of endemic disease and on the assays employed in routine serological or NAT screening. Screening of anti-HBc is feasible in non-endemic areas, but would cost an unnecessary loss of blood donations in endemic areas (where nearly 90% of adults are positive for both anti-HBc and anti-HBs due to past exposure to HBV).
] provide an excellent summary of the prevalence of serological markers in HBsAg negative blood donors in different regions of the world. The studies of prevalence in North America reveal that HBV DNA was detected in 0.1%-1.05% of those who were HBsAg negative and anti-HBc-positive (with or without anti-HBs) and that HBV DNA was detected in 2.03%-2.8% in the anti-HBc only category (no anti-HBs)[30-34
]. The studies of prevalence in Europe reveals that HBV DNA was detected in 0%-1.59% of those who were HBsAg negative and anti-HBc-positive (with or without anti-HBs) and HBV DNA was not detected in patients who were anti-HBc only[35-38
]. In the study of Allain et al[35
] no occult hepatitis B was detected in any of the samples because the level of sensitivity was only approximately 1300 copies/mL. The studies of prevalence in the Middle East and Asia revealed that HBV DNA was detected in 1.09%-3% of those who were HBsAg negative and anti-HBc-positive (with or without anti-HBs) and that HBV DNA was detected in 8.1% in the anti-HBc only category (no anti-HBs)[39-41
There are few studies about OBI prevalence in the general population. Minuk et al[42
] detected a prevalence of OBI in 18% of those with serological evidence of previous HBV infection and in 8% of HBV seronegative individuals. Kim et al[43
] found HBV DNA in 16% of Korean healthy subjects with normal transaminase values and who were HBV/HCV negative. Hui et al[44
] detected occult HBV genomes in 15% of healthy hematopoietic stem cell donors from Hong-Kong. Raimondo et al[45
] investigated the prevalence of OBI in subjects free from liver disease through the analysis of liver DNA extracts by performing four different in-house nested-PCR amplification assays. HBV DNA sequences were detected in liver tissues from 16 of the 98 cases examined (16.3%). DNA was detected in 10 of the 16 (62.5%) anti-HBc positive cases vs
6 of the 82 (7.3%) HBV marker negative cases, so OBI status was strongly related with the anti-HBV antibody positive status.
Although studies on OBI prevalence have been extensive, the precise prevalence of this clinical entity remains very difficult to define for several reasons. These studies show that OBI prevalence seems to be higher among subjects at high risk of HBV infection and with liver disease than among individuals at low risk of infection and without liver disease. In general about 20% of OBI individuals are negative for all serological markers, and 80% are positive for serological markers of previous infection. Most studies show that OBI is usually associated with low levels of HBV DNA. The importance of this entity is that OBI may have significant impact in several clinical contexts. It might favour the progression of liver fibrosis and the development of hepatocellular carcinoma in patients with additional causes of liver damage; OBI may become reactivated when an immunosuppresive status occurs; and it may be transmitted through blood transfusion and organ transplantation. While awating for more sensitive methods for blood HBV DNA measurement, anti-HBc should be recommended in patients undergoing chemotherapy or immunosuppresive treatments as well as all organ donors.
Raimondo G, Pollicino T, Cacciola I, Squadrito G. Occult hepatitis B virus infection. J Hepatol.
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.
Fukuda R, Ishimura N, Niigaki M, Hamamoto S, Satoh S, Tanaka S, Kushiyama Y, Uchida Y, Ihihara S, Akagi S. Serologically silent hepatitis B virus coinfection in patients with hepatitis C virus-associated chronic liver disease: clinical and virological significance. J Med Virol.
Bréchot C, Thiers V, Kremsdorf D, Nalpas B, Pol S, Paterlini-Bréchot P. Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely "occult"?. Hepatology.
Berasain C, Betés M, Panizo A, Ruiz J, Herrero JI, Civeira MP, Prieto J. Pathological and virological findings in patients with persistent hypertransaminasaemia of unknown aetiology. Gut.
Chemin I, Zoulim F, Merle P, Arkhis A, Chevallier M, Kay A, Cova L, Chevallier P, Mandrand B, Trépo C. High incidence of hepatitis B infections among chronic hepatitis cases of unknown aetiology. J Hepatol.
Siagris D, Christofidou M, Triga K, Pagoni N, Theocharis GJ, Goumenos D, Lekkou A, Thomopoulos K, Tsamandas AC, Vlachojannis J. Occult hepatitis B virus infection in hemodialysis patients with chronic HCV infection. J Nephrol.
Goral V, Ozkul H, Tekes S, Sit D, Kadiroglu AK. Prevalence of occult HBV infection in haemodialysis patients with chronic HCV. World J Gastroenterol.
Fabrizi F, Messa PG, Lunghi G, Aucella F, Bisegna S, Mangano S, Villa M, Barbisoni F, Rusconi E, Martin P. Occult hepatitis B virus infection in dialysis patients: a multicentre survey. Aliment Pharmacol Ther.
Minuk GY, Sun DF, Greenberg R, Zhang M, Hawkins K, Uhanova J, Gutkin A, Bernstein K, Giulivi A, Osiowy C. Occult hepatitis B virus infection in a North American adult hemodialysis patient population. Hepatology.
Kanbay M, Gur G, Akcay A, Selcuk H, Yilmaz U, Arslan H, Boyacioglu S, Ozdemir FN. Is hepatitis C virus positivity a contributing factor to occult hepatitis B virus infection in hemodialysis patients?. Dig Dis Sci.
Besisik F, Karaca C, Akyüz F, Horosanli S, Onel D, Badur S, Sever MS, Danalioglu A, Demir K, Kaymakoglu S. Occult HBV infection and YMDD variants in hemodialysis patients with chronic HCV infection. J Hepatol.
Gwak GY, Huh W, Lee DH, Min BH, Koh KC, Kim JJ, Oh HY. Occult hepatitis B virus infection in chronic hemodialysis patients in Korea. Hepatogastroenterology.
Motta JS, Mello FC, Lago BV, Perez RM, Gomes SA, Figueiredo FF. Occult hepatitis B virus infection and lamivudine-resistant mutations in isolates from renal patients undergoing hemodialysis. J Gastroenterol Hepatol.
Yakaryilmaz F, Gurbuz OA, Guliter S, Mert A, Songur Y, Karakan T, Keles H. Prevalence of occult hepatitis B and hepatitis C virus infections in Turkish hemodialysis patients. Ren Fail.
Mina P, Georgiadou SP, Rizos C, Dalekos GN, Rigopoulou EI. Prevalence of occult hepatitis B virus infection in haemodialysis patients from central Greece. World J Gastroenterol.
Sav T, Gursoy S, Torun E, Sav NM, Unal A, Oymak O, Utas C. Occult HBV infection in continuous ambulatory peritoneal dialysis and hemodialysis patients. Ren Fail.
Núñez M, Ríos P, Pérez-Olmeda M, Soriano V. Lack of 'occult' hepatitis B virus infection in HIV-infected patients. AIDS.
Hofer M, Joller-Jemelka HI, Grob PJ, Lüthy R, Opravil M. Frequent chronic hepatitis B virus infection in HIV-infected patients positive for antibody to hepatitis B core antigen only. Swiss HIV Cohort Study. Eur J Clin Microbiol Infect Dis.
Filippini P, Coppola N, Pisapia R, Scolastico C, Marrocco C, Zaccariello A, Nacca C, Sagnelli C, De Stefano G, Ferraro T. Impact of occult hepatitis B virus infection in HIV patients naive for antiretroviral therapy. AIDS.
Pogány K, Zaaijer HL, Prins JM, Wit FW, Lange JM, Beld MG. Occult hepatitis B virus infection before and 1 year after start of HAART in HIV type 1-positive patients. AIDS Res Hum Retroviruses.
Neau D, Winnock M, Jouvencel AC, Faure M, Castéra L, Legrand E, Lacoste D, Ragnaud JM, Dupon M, Fleury H. Occult hepatitis B virus infection in HIV-infected patients with isolated antibodies to hepatitis B core antigen: Aquitaine cohort, 2002-2003. Clin Infect Dis.
Santos EA, Yoshida CF, Rolla VC, Mendes JM, Vieira IF, Arabe J, Gomes SA. Frequent occult hepatitis B virus infection in patients infected with human immunodeficiency virus type 1. Eur J Clin Microbiol Infect Dis.
Wagner AA, Denis F, Weinbreck P, Loustaud V, Autofage F, Rogez S, Alain S. Serological pattern 'anti-hepatitis B core alone' in HIV or hepatitis C virus-infected patients is not fully explained by hepatitis B surface antigen mutants. AIDS.
Gonçales FL Jr, Pereira JS, Da Silva C, Thomaz GR, Pavan MH, Fais VC, Magna LA, Gonçales NS. Hepatitis B virus DNA in sera of blood donors and of patients infected with hepatitis C virus and human immunodeficiency virus. Clin Diagn Lab Immunol.
Rodríguez-Torres M, Gonzalez-Garcia J, Bräu N, Solá R, Moreno S, Rockstroh J, Smaill F, Mendes-Correa MC, DePamphilis J, Torriani FJ. Occult hepatitis B virus infection in the setting of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection: clinically relevant or a diagnostic problem?. J Med Virol.
Lo Re V 3rd, Frank I, Gross R, Dockter J, Linnen JM, Giachetti C, Tebas P, Stern J, Synnestvedt M, Localio AR. Prevalence, risk factors, and outcomes for occult hepatitis B virus infection among HIV-infected patients. J Acquir Immune Defic Syndr.
Cohen Stuart JW, Velema M, Schuurman R, Boucher CA, Hoepelman AI. Occult hepatitis B in persons infected with HIV is associated with low CD4 counts and resolves during antiretroviral therapy. J Med Virol.
Hollinger FB. Hepatitis B virus infection and transfusion medicine: science and the occult. Transfusion.
Kleinman SH, Kuhns MC, Todd DS, Glynn SA, McNamara A, DiMarco A, Busch MP. Frequency of HBV DNA detection in US blood donors testing positive for the presence of anti-HBc: implications for transfusion transmission and donor screening. Transfusion.
Kleinman SH, Strong DM, Tegtmeier GG, Holland PV, Gorlin JB, Cousins C, Chiacchierini RP, Pietrelli LA. Hepatitis B virus (HBV) DNA screening of blood donations in minipools with the COBAS AmpliScreen HBV test. Transfusion.
Linauts S, Saldanha J, Strong DM. PRISM hepatitis B surface antigen detection of hepatits B virus minipool nucleic acid testing yield samples. Transfusion.
Chevrier MC, St-Louis M, Perreault J, Caron B, Castilloux C, Laroche J, Delage G. Detection and characterization of hepatitis B virus of anti-hepatitis B core antigen-reactive blood donors in Quebec with an in-house nucleic acid testing assay. Transfusion.
O'Brien SF, Fearon MA, Yi QL, Fan W, Scalia V, Muntz IR, Vamvakas EC. Hepatitis B virus DNA-positive, hepatitis B surface antigen-negative blood donations intercepted by anti-hepatitis B core antigen testing: the Canadian Blood Services experience. Transfusion.
Allain JP, Hewitt PE, Tedder RS, Williamson LM. Evidence that anti-HBc but not HBV DNA testing may prevent some HBV transmission by transfusion. Br J Haematol.
Hennig H, Puchta I, Luhm J, Schlenke P, Goerg S, Kirchner H. Frequency and load of hepatitis B virus DNA in first-time blood donors with antibodies to hepatitis B core antigen. Blood.
Hourfar MK, Jork C, Schottstedt V, Weber-Schehl M, Brixner V, Busch MP, Geusendam G, Gubbe K, Mahnhardt C, Mayr-Wohlfart U. Experience of German Red Cross blood donor services with nucleic acid testing: results of screening more than 30 million blood donations for human immunodeficiency virus-1, hepatitis C virus, and hepatitis B virus. Transfusion.
Brojer E, Grabarczyk P, Liszewski G, Mikulska M, Allain JP, Letowska M. Characterization of HBV DNA+/HBsAg- blood donors in Poland identified by triplex NAT. Hepatology.
Bhatti FA, Ullah Z, Salamat N, Ayub M, Ghani E. Anti-hepatits B core antigen testing, viral markers, and occult hepatitis B virus infection in Pakistani blood donors: implications for transfusion practice. Transfusion.
Nantachit N, Thaikruea L, Thongsawat S, Leetrakool N, Fongsatikul L, Sompan P, Fong YL, Nichols D, Ziermann R, Ness P. Evaluation of a multiplex human immunodeficiency virus-1, hepatitis C virus, and hepatitis B virus nucleic acid testing assay to detect viremic blood donors in northern Thailand. Transfusion.
Satake M, Taira R, Yugi H, Hino S, Kanemitsu K, Ikeda H, Tadokoro K. Infectivity of blood components with low hepatitis B virus DNA levels identified in a lookback program. Transfusion.
Minuk GY, Sun DF, Uhanova J, Zhang M, Caouette S, Nicolle LE, Gutkin A, Doucette K, Martin B, Giulivi A. Occult hepatitis B virus infection in a North American community-based population. J Hepatol.
Kim SM, Lee KS, Park CJ, Lee JY, Kim KH, Park JY, Lee JH, Kim HY, Yoo JY, Jang MK. Prevalence of occult HBV infection among subjects with normal serum ALT levels in Korea. J Infect.
Hui CK, Sun J, Au WY, Lie AK, Yueng YH, Zhang HY, Lee NP, Hou JL, Liang R, Lau GK. Occult hepatitis B virus infection in hematopoietic stem cell donors in a hepatitis B virus endemic area. J Hepatol.
Raimondo G, Navarra G, Mondello S, Costantino L, Colloredo G, Cucinotta E, Di Vita G, Scisca C, Squadrito G, Pollicino T. Occult hepatitis B virus in liver tissue of individuals without hepatic disease. J Hepatol.