This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Nicola Coppola, Lorenzo Onorato, Mariantonietta Pisaturo, Margherita Macera, Salvatore Martini, Evangelista Sagnelli, Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, 80131 Naples, Italy
Mariantonietta Pisaturo, Division of Infectious Diseases, AORN Sant’Anna e San Sebastiano di Caserta, 81100 Caserta, Italy
Caterina Sagnelli, Department of Clinical and Experimental Medicine and Surgery “F. Magrassi e A. Lanzara”, Second University of Naples, 80131 Naples, Italy
ORCID number: $[AuthorORCIDs]
Author contributions: Coppola N, Onorato L, Pisaturo M, Macera M, Sagnelli C, Martini S and Sagnelli E made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published.
Conflict-of-interest statement: All the authors of the manuscript declare that they have no conflict of interest in connection with this paper.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Nicola Coppola, Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Via L. Armanni 5, 80131 Naples, Italy. email@example.com
Telephone: +81-5666719 Fax: +81-5666013
Received: April 15, 2015 Peer-review started: April 18, 2015 First decision: June 2, 2015 Revised: June 28, 2015 Accepted: September 14, 2015 Article in press: September 14, 2015 Published online: November 14, 2015
The development of sensitive assays to detect small amounts of hepatitis B virus (HBV) DNA has favored the identification of occult hepatitis B infection (OBI), a virological condition characterized by a low level of HBV replication with detectable levels of HBV DNA in liver tissue but an absence of detectable surface antigen of HBV (HBsAg) in serum. The gold standard to diagnose OBI is the detection of HBV DNA in the hepatocytes by highly sensitive and specific techniques, a diagnostic procedure requiring liver tissue to be tested and the use of non-standardized non-commercially available techniques. Consequently, in everyday clinical practice, the detection of anti-hepatitis B core antibody (anti-HBc) in serum of HBsAg-negative subjects is used as a surrogate marker to identify patients with OBI. In patients with chronic hepatitis C (CHC), OBI has been identified in nearly one-third of these cases. Considerable data suggest that OBI favors the increase of liver damage and the development of hepatocellular carcinoma (HCC) in patients with CHC. The data from other studies, however, indicate no influence of OBI on the natural history of CHC, particularly regarding the risk of developing HCC.
Core tip: Occult hepatitis B infection (OBI) is a virological condition characterized by a low level of hepatitis B virus (HBV) replication with HBV DNA detectable in liver tissue in the absence of detectable surface antigen of HBV in serum. Some studies indicate that OBI may favor the increase of liver fibrosis and the development of hepatocellular carcinoma in patients with chronic hepatitis C, whereas other investigations refute this. Here, we review all the available data on this topic and discuss the possible influence of OBI on the natural course of chronic hepatitis C.
Citation: Coppola N, Onorato L, Pisaturo M, Macera M, Sagnelli C, Martini S, Sagnelli E. Role of occult hepatitis B virus infection in chronic hepatitis C. World J Gastroenterol 2015; 21(42): 11931-11940
Approximately 170 million individuals are chronically infected with hepatitis C virus (HCV) worldwide[1-4]. HCV is a small, enveloped, positive-sense, single-stranded RNA virus of the genus Hepacivirus of the Flaviviridae family. Phylogenetic analysis of HCV isolates has generated the viral classification into six major genotypes (from 1 to 6) and more than 100 subtypes[5,6]. HCV is transmitted by percutaneous exposure to infected blood through intravenous drug injection and invasive medical procedures, and by permucosal exposure through unprotected intercourse with multiple partners[7,8], particularly in human immunodeficiency virus (HIV)-positive men who have sex with men[9-12].
HCV causes acute hepatitis that is frequently asymptomatic, and in its symptomatic form, it is characterized by nausea, malaise, and jaundice. The acute HCV infection resolves spontaneously in about one-third of the cases[13,14], whereas the remaining two-thirds remain infected, circulate anti-HCV and HCV RNA, and usually show an indolent course or a slow progression to liver cirrhosis and hepatocellular carcinoma (HCC). In some cases, however, spontaneous acute exacerbations may develop, characterized by one or more peaks of the aminotransferase serum levels above the previous values[16-22], which can frequently induce a deterioration of the liver disease. In some cases the progression to liver cirrhosis and HCC is rapid, particularly when co-morbidities, an unfavorable genetic background, and unsafe lifestyle factors are present. Indeed, the outcome of chronic hepatitis C (CHC) is influenced by associated host factors (sex, age at infection, routes of transmission, immune response, genetic background), viral factors (HCV genotype and viral quasispecies), co-morbidities (viral co-infection, insulin-resistance, liver steatosis, immunosuppressive clinical condition) and lifestyle factors (alcohol intake)[23-30].
The development of sensitive assays to detect small amounts of hepatitis B virus (HBV) DNA has favored the identification of occult HBV infection (OBI), a virological condition characterized by a low level of HBV replication with HBV DNA detectable in the liver cells in the absence of detectable surface antigen of HBV (HBsAg) in serum. In patients with CHC, OBI has been identified in about one-third of HBsAg-negative/anti-HCV-positive subjects in the Mediterranean Basin and in more than 50% in East Asian countries[31-36]. Considerable data suggest that in patients with CHC, OBI may contribute to chronic liver damage and to the development of HCC[24,31,37-40]. Other studies, however, indicate that OBI does not influence the natural history of HCV infection, particularly as regards the risk of HCC development[41-43]. In this review article, which takes into account all the available literature data, the possible role of OBI in modifying the clinical course of CHC is evaluated and discussed.
DEFINITION OF OBI
OBI has been defined as the presence of viral DNA in the liver tissue (regardless of HBV DNA detectability in serum) of individuals testing negative for serum HBsAg. The gold standard to diagnose OBI is the detection of HBV DNA in the hepatocytes by highly sensitive and specific techniques [real-time polymerase chain reaction (PCR), nested PCR, and the use of oligonucleotide primers specific for different HBV genomic regions], a diagnostic procedure requiring liver tissue to be tested and the use of non-standardized non-commercially available techniques. Consequently, in everyday clinical practice, the detection of anti-hepatitis B core antibody (anti-HBc) in serum of HBsAg-negative subjects, a sign of previous acute hepatitis B (AHB), is used as a surrogate serum marker to identify subjects with OBI[39,43-49]. This option is supported by the observation that in patients experiencing immunosuppression, OBI, as defined by the presence of HBV DNA in liver tissue, mostly occurs in HBsAg-negative/anti-HBc-positive patients[44,50,51]. The data from a previous investigation on 89 HBsAg-negative patients with CHC showed the presence of HBV DNA in plasma, peripheral blood mononuclear cells, and/or liver tissue in 60% of the anti-HBs/anti-HBc-positive patients, in 80% of the anti-HBs-negative/anti-HBc-positive patients, and in 10% of those lacking both antibodies.
MECHANISMS OF LIVER DAMAGE BY OBI
In some cases, an underhand activity of the HBV genome is the persistence of mild hepatocellular necrosis for years after the resolution of self-limiting AHB[52,53]. The mechanism of liver damage due to OBI is still unclear, but there is some evidence that viral factors may play a role in its development and in the related liver damage. In fact, the persistent synthesis of minute undetectable amounts of the virus or other viral transcripts produced by the HBV covalently closed circular DNA (cccDNA) seems capable of maintaining the HBV-specific memory T-cell response[33,54] and the production of cytokines, such as tumor necrosis factor-α and interferon-γ[55,56]. In addition, mutations in the X region of HBV may reduce the ability of the X protein to transactivate host cellular proteins essential for viral replication, which may lead to the reduction of HBV DNA replication and the lack of HBsAg serum expression.
We should remember, however, that a rare escape mutation in the S region decreases the reactivity in the HBsAg detection assays and is responsible for an “overt” HBsAg-negative infection that might mimic OBI.
OBI AND THE PROGRESSION OF LIVER FIBROSIS
The impact of OBI, as detected by the presence of serum anti-HBc, on the progression of liver fibrosis in patients with CHC
As mentioned above, the detection of serum anti-HBc has been used as a surrogate marker of the presence of liver HBV DNA to detect OBI in numerous investigations exploring the correlation between this virological condition and liver fibrosis in patients with CHC (Table 1). In the year 2000, our group published a cross-sectional, case-control study on 174 Caucasian HBsAg-negative CHC patients. We showed that the prevalence of cases with cirrhosis in the anti-HBc-positive subgroup was significantly higher than in the anti-HBc-negative subgroup, suggesting a role of OBI in fibrosis progression. Similar data were obtained in a cross-sectional study performed in the same period by De Maria et al on 285 HCV-infected patients. A few years later, a cross-sectional study confirmed the relationship between the presence of anti-HBc and liver cirrhosis in 119 Italian anti-HCV- positive/HBsAg-negative patients. A study on 129 Portuguese anti-HCV-positive patients published in 2005 found an independent association between previous HBV infection and biopsy-proven liver cirrhosis. Subsequent studies further confirmed the unfavorable influence of OBI, as detected by the presence of anti-HBc in HBsAg-negative patients, on the clinical course of CHC. A cross-sectional Brazilian study found OBI was a predictor of significant necroinflammation and fibrosis; El-Sherif et al demonstrated that the prevalence of cases with advanced liver disease was higher in patients with OBI than in those without. Coppola et al demonstrated that OBI was an independent predictor of HCV-related cirrhosis in a cross-sectional study on 222 patients from southern Italy.
Table 1 The studies evaluating the role of anti-HBc in the development of cirrhosis in HBsAg-negative patients with chronic hepatitis C.
1Hazard ratio for progression to cirrhosis in HBsAb/HBcAb+ patients;
2Advanced fibrosis (Scheuer score > 2);
3Advanced fibrosis (Metavir score F2-F4). NS: Not significant.
Conflicting data have been published by other authors. Verbaan et al did not find any association between OBI and the progression to cirrhosis in 99 CHC patients, whereas in an Egyptian study, patients with OBI were more likely than those without to show HCV-related cirrhosis. No association was observed between serum anti-HBc and the degree of liver fibrosis in a study from Spain or between anti-HBc and the entity of necroinflammation or fibrosis in a French study.
The impact of OBI, as detected by the presence of HBV DNA in liver tissue, plasma, or peripheral blood mononuclear cells, on the progression of liver fibrosis in patients with CHC
Table 2 shows the data from several studies on the relationship between the degree of liver fibrosis and the presence of OBI, as demonstrated by detecting HBV DNA in the liver tissue, plasma, or peripheral blood mononuclear cells (PBMC) of HBsAg-negative patients with CHC (Table 2). One of the first studies to suggest a clinical impact of OBI was a cross-sectional study published in 1999 by Cacciola et al, which showed in 200 CHC patients that 33.3% of those with detectable liver HBV DNA had cirrhosis whereas only 19.4% of HBV-DNA-negative patients did. Similar data were observed in 203 HCV-infected patients in a French study published in 2007, in which patients with plasma HBV-DNA showed more advanced fibrosis (P < 0.001) than those who were HBV-DNA-negative. In 2008, Matsuoka et al tested 468 Japanese HBsAg-negative patients with CHC for the presence of plasma HBV DNA and found over a mean follow-up period of 6.7 years that cirrhosis and HCC occurred more frequently in those with OBI than in those without. These data were confirmed in a prospective study from Italy, in which HBV DNA was detected in the liver tissue of 326 CHC patients, and progression to cirrhosis or development of HCC were more frequent in those with OBI than in those without.
Table 2 The studies evaluating the role of hepatitis B virus DNA in serum and/or liver tissue in the development of cirrhosis in surface antigen of hepatitis B virus-negative patients with chronic hepatitis C.
Conflicting data, however, have come from several studies, with all but one detecting HBV DNA only in plasma. In a Japanese study on 65 HCV-infected patients, liver cirrhosis was detected with a similar frequency in CHC patents with or without OBI. In 2004, Toberson et al reported no association between OBI and the grading or staging in 180 anti-HCV-positive drug users. A cross-sectional study published in the same year on 59 Brazilian patients showed a similar degree of liver fibrosis in those with or without OBI. Hui et al[72,73] published in 2006 two retrospective cohort studies on 74 CHC patients and 118 subjects with a recurrent HCV infection after liver transplantation, respectively. In both studies, liver fibrosis, as detected by comparing two consecutive liver biopsies, showed a similar increase in patients with or without OBI. In addition, Sagnelli et al did not find any association between the degree of liver fibrosis and OBI in a prospective study where OBI was assessed through the detection of HBV DNA in plasma, PBMC, and liver tissue in 89 patients with CHC. Finally, Emara et al studied 155 Egyptian CHC patients and found the prevalence of cases with cirrhosis in patients with circulating HBV DNA was significantly lower than in those without.
OBI AND THE OCCURRENCE OF HCC
There is biological, epidemiological, and clinical evidence demonstrating that the oncogenic potential of HBV may induce the development of HCC both in patients with cirrhosis and in those with a milder liver disease. Chronic HBV infection accounts for approximately 50% of the total cases and for virtually all childhood HCC, and prospective cohort studies showed a 5- to 100-fold increase in the risk of developing HCC among HBsAg carriers compared with uninfected subjects. In spite of this, the role of OBI in the development of HCC in patients with chronic hepatitis due to etiological agents other than HBV, firstly HCV, is still a matter of debate in the scientific community. Using anti-HBc positivity or the presence of HBV DNA in plasma or liver tissue as a sign of OBI, several research groups have investigated the role of OBI in the development of HCC in HBsAg-negative patients with CHC.
The impact of OBI, as detected by the presence of serum anti-HBc, on the development of HCC in patients with CHC
The studies that evaluated the impact of OBI, as detected by the presence of anti-HBc in serum, on the development of HCC are listed in Table 3. In 1996, Chiba et al published data from a cohort study on 412 Japanese patients with CHC with or without cirrhosis and showed a higher incidence of HCC in those with OBI than in those without (23.7% vs 7.5%, P = 0.02). The same authors reported similar results in a cross-sectional study on 204 cirrhotic patients. In 1999, a case-control study on 51 Australian patients with CHC with or without cirrhosis showed a correlation between the occurrence of HCC and male gender, lower serum albumin level, and anti-HBc positivity. In the same year, Marusawa et al published a study on 2014 patients with CHC with or without cirrhosis and showed that patients with OBI had a significantly higher rate of HCC than those without (34.7% vs 18.8%). Similar results were reported in a cohort study on 459 Japanese patients followed up for a mean period of 6.6 years, where the incidence of HCC correlated with the age of the patients, the degree of liver fibrosis, alanine aminotransferase (ALT) levels and anti-HBc positivity. Another Japanese cohort study on 74 CHC patients showed a correlation between the incidence of HCC and anti-HBc positivity. Ikeda et al performed a prospective study on 872 Japanese CHC patients and observed in those with liver cirrhosis a significantly higher occurrence of HCC in those with OBI than in those without, a difference not observed in patients with a lower degree of liver fibrosis. Adachi et al followed up 123 Japanese cirrhotic patients for a mean period of 53.3 mo and identified as independent predictors of HCC development male gender, higher α-fetoprotein and ALT serum values, and the presence in serum of anti-HBc but not HBV DNA. A case-control study recently conducted by Reddy et al in North America on 459 anti-HCV-positive patients with CHC showed a significantly higher frequency of HCC in those with OBI than in those without.
Table 3 The studies evaluating the role of anti-hepatitis B core in the development of hepatocellular carcinoma in surface antigen of hepatitis B virus-negative patients with chronic hepatitis C.
1Incidence Rate Ratio for HCC in patients with chronic hepatitis;
2Incidence Rate Ratio for HCC in patients with cirrhosis. CH: Chronic hepatitis; CLD: Chronic liver disease; NS: Not significant; HCC: Hepatocellular carcinoma; HBc: Hepatitis B core.
Several studies, however, produced different results. A prospective investigation on 61 CHC patients found no difference in HCC occurrence between groups of patients with or without previous exposure to HBV. The cohort study conducted in 1998 by the Italian IFN-α Hepatocellular Carcinoma Study Group on 451 anti-HCV-positive subjects showed a similar incidence of HCC in anti-HBc-positive and -negative cases. In 1997, a Japanese study on 502 patients found a similar frequency of HCC in anti-HBc-positive and anti-HBc-negative patients. Hiraoka et al in 2003 and Hasegawa et al in 2005 also published similar data. Likewise, Bruno et al demonstrated that anti-HBc positivity was not independently associated with HCC occurrence in 163 Italian consecutive cirrhotic patients with HCV infection followed up for a median period of 10.7 years. Similarly, Stroffolini et al found no association between serum anti-HBc positivity and HCC development in a multicenter retrospective cohort study of 693 Italian cirrhotic patients. This association was not found also in two cross-sectional studies, one conducted in Lebanon and one in Brazil. In a cohort study on 1262 Japanese HCV patients, anti-HBc positivity was associated with the development of HCC in a univariate analysis but not in a multivariate analysis considering age and gender as confounding factors. Finally, Tsubouchi et al published in 2013 the results of a prospective study on 400 anti-HCV-positive patients and showed no difference in the incidence of HCC and of cumulative liver-related mortality in patients with and without OBI.
The impact of OBI, as detected by the presence of HBV DNA in serum or liver tissue, on the development of HCC in patients with CHC
The studies listed in Table 4 investigated the correlation between HBV-DNA positivity in plasma or in liver tissue and the development of HCC in CHC patients (Table 4). Pollicino et al tested for HBV DNA in the tumorous tissue of 73 patients with CHC and HCC and a liver sample of 153 CHC patients used as controls and observed a significant association between OBI and HCC, irrespective of age or gender. In a cross-sectional study published in 2004, Tanaka et al demonstrated a significantly higher frequency of cases with HCC in CHC patients with plasma HBV-DNA positivity than in those without. Branco et al studied 26 Brazilian CHC patients, 20 with HCV-related HCC and 20 healthy controls, for HBV DNA in serum and for HBsAg and HBcAg immunochemistry in liver tissue and found a higher prevalence of HCC in the 10 patients with OBI than in the 56 without (70% vs 23%). Seeking HBV DNA in the liver tissue of 124 CHC patients followed up for a mean period of 82.8 mo, Squadrito et al found a significant association between OBI and HCC occurrence, a finding confirmed in a study they published more recently. In 2008, a cohort study enrolling 141 Japanese CHC patients identified OBI as an independent predictor of HCC development.
Table 4 The studies evaluating the role of hepatitis B virus DNA in serum and/or liver tissue in the development of hepatocellular carcinoma in surface antigen of hepatitis B virus-negative patients with chronic hepatitis C.
1OBI assessed with immunochemistry for HBsAg and/or HBcAg. OBI: Occult HBV infection; CH: Chronic hepatitis; CLD: Chronic liver disease; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma.
Some published studies, however, report conflicting data. A prospective study by Obika et al on 167 patients with CHC showed a similar incidence rate of HCC over a mean follow-up of 42.5 mo in patients with or without HBV DNA in liver tissue (8% vs 7%, respectively). In 2008, Shetty et al published a study on 56 patients selected for orthotopic liver transplantation (OLT), 44 of whom underwent OLT. Serum HBV DNA was detected in 28% of the 56, and liver HBV DNA was detected in 50% of the 44. Explant-proven HCC was found in 12 of the 22 (54.5%) patients with OBI and in eight of the 22 (36.3%) without, a difference not statistically significant. Lastly, Lok et al tested for HBV DNA in frozen liver samples of 83 CHC patients, 28 with HCC and 55 controls, and found no association between OBI and HCC.
The clinical impact of OBI on the natural history of CHC has been extensively investigated, but the available data are conflicting and do not allow for conclusions to be drawn on this topic. One of the main reasons for this inconsistency is the heterogeneity of the methods used to detect OBI. In fact, the detection of HBV DNA in liver tissue of HBsAg-negative subjects can be considered of high sensitivity and high specificity, and that of HBV DNA in plasma of high specificity and moderate sensitivity. In addition, the detection of anti-HBc in serum should be considered of moderate specificity and moderate sensitivity in this setting, although anti-HBc-negative subjects may show HBV DNA in the liver tissue. Furthermore, the variety of diagnostic molecular assays used to identify HBV DNA in plasma and liver tissue of HBsAg-negative subjects possess different sensitivities, bringing considerable heterogeneity in the results. Indeed, in the majority of studies, anti-HBc in serum or HBV DNA in plasma was used to detect OBI, since this method is cheaper, less invasive, and less time-consuming than the detection of HBV DNA in the liver tissue.
Other reasons for the substantial variability in the prevalence of OBI in published studies may be the differences in the extent of the spread of HBV infection in the various geographical areas, the variability in the viral characteristics, and the heterogeneity of the enrolment criteria regarding age, gender, immunological and ethnic background, and social habits of the subjects examined.
In addition, OBI itself is a virological condition of different origins; most patients having a self-limiting AHB and a minority from the pool of HBsAg chronic carriers, of whom nearly 1% per year clear serum HBsAg. Subjects with OBI of different origins may be present in different proportions in the studies published, and OBI itself may have a different outcome and a different impact on the clinical course of CHC in relation to its origin.
In light of this, we should conclude that the present knowledge on the clinical impact of OBI on the progression of liver fibrosis and on the development of HCC is still insufficient.
In order to reduce the effect of different methods with different sensitivity and specificity used to detect OBI in the published studies, we performed a comprehensive analysis of the studies in which OBI was identified by the detection of HBV DNA in the liver tissue, but the results remained conflicting. In fact, regarding the progression to cirrhosis, we have only three studies, two from the same Italian group[31,69] showing a higher rate of patients with cirrhosis in CHC with OBI than in those without, and one from another Italian group showing no difference. Regarding the development of HCC, six studies were analyzed, three of which were from the same Italian research group[39,40,69], showing a higher rate of patients with HCC in the group of patients with OBI than in those without, whereas the other three studies, one from Japan and two from the United States[42,43], showed no difference. The selection criteria were certainly different from one study to another, but the methods to detect HBV DNA in the liver were similar, albeit not identical. Therefore, the question whether OBI might influence the natural course of CHC remains unanswered.
A strong contribution to defining the clinical impact of OBI could come from a prospective international study considering a large number of HBsAg-negative patients with CHC selected with pre-established criteria and using as sign of OBI the detection of HBV DNA in the liver tissue performed with a highly sensitive technique in a single, high standard laboratory.
No standardized strategy, at least to our best knowledge, is at present recommended for the management of OBI in patients with CHC. In particular, because of the uncertainty surrounding the clinical impact of OBI, it is not clear whether close monitoring is an adequate measure or whether the administration of an anti-HBV nucleot(s)ide to prevent both the progression of fibrosis and the onset of HCC is necessary. In this case, the low cost of the anti-HBV nucleoside lamivudine, which is now obsolete in other HBV treatment settings because of its low genetic barrier and the consequent high risk of inducing viral resistance, might be the drug of choice to suppress the low level of HBV replication characterizing OBI.
In conclusion, some studies indicate that OBI unfavorably affects the progression of liver fibrosis and the development of HCC in patients with CHC, an observation not confirmed in other investigations. The data from prospective studies applying a careful selection of patients and a highly sensitive, standardized method to identify HBV DNA in the liver tissue may help clarify this important issue.
P- Reviewer: Inoue K S- Editor: Yu J L- Editor: Filipodia E- Editor: Liu XM
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