Occult Hepatitis B Virus Infection Prevalence Among Different Populations of Iran: A Systematic Review and Meta-Analysis

AUTHORS

Mohammad Reza Hedayati-Moghaddam ORCID 1 , * , Hossein Soltanian 1 , Masoud Behzadifar 2

1 Blood Borne Infections Research Centre, Academic Centre for Education, Culture and Research (ACECR), Razavi Khorasan Branch, Mashhad, Iran

2 Health Management and Economics Research Center, Iran University of Medical Sciences, Tehran, Iran

How to Cite: Hedayati-Moghaddam M R, Soltanian H, Behzadifar M. Occult Hepatitis B Virus Infection Prevalence Among Different Populations of Iran: A Systematic Review and Meta-Analysis, Hepat Mon. 2020 ; 20(6):e101722. doi: 10.5812/hepatmon.101722.

ARTICLE INFORMATION

Hepatitis Monthly: 20 (6); e101722
Published Online: June 2, 2020
Article Type: Systematic Review
Received: February 10, 2020
Revised: May 13, 2020
Accepted: May 15, 2020
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Abstract

Context: Various frequency rates of occult hepatitis B virus infection (OBI) are reported from different parts of Iran. This systematic review and meta-analysis aimed to characterize the OBI epidemiology in Iran and estimate the pooled prevalence among different populations.

Evidence Acquisition: Nine international and Persian electronic databases, as well as some conference proceedings, were searched. Original cross-sectional studies up to December 2018 were included if they investigated the prevalence of OBI by the detection of serum hepatitis B virus surface antigen and hepatitis B virus nucleic acid in at least 30 samples selected with any sampling methods. Comprehensive meta-analysis software was used to analyze the data, and Cochran’s Q-test and I-square statistics were applied to assess the heterogeneity. Meta-regression analysis was performed to assess the impact of the year of study on the OBI frequency. A P value < 0.05 was considered as the level of significance.

Results: Of 412 citations found in electronic sources and 35 relevant citations added by searching the gray literature, 83 non-duplicated non-overlapping studies were evaluated. A total of 55 documents comprising 14,485 individuals from 16 provinces met the inclusion criteria and were used in the analysis. The prevalence of OBI considerably varied in different parts of the country with the highest prevalence (63.1%) reported among the HIV-positive population in Fars province. The rates of the OBI prevalence were estimated at 0.06% (95% CI: 0.02 - 0.16%) among blood donors (BDs) regardless of their anti-HBc status, 7.90% (95% CI: 4.33 - 13.99%) among anti-HBc positive BDs, 2.49% (95% CI: 1.2 - 4.81%) among hemodialysis (HD) patients, 4.44% (95% CI: 1.56 - 12.02%) among HIV-positive patients, and 7.76% (95% CI: 4.57 - 12.86%) among HCV-positive patients. No significant trends were observed in OBI prevalence rates among different groups over time (P > 0.05).

Conclusions: This review revealed high rates of OBI prevalence among high-risk populations in Iran. It is strongly suggested that occult hepatitis B be investigated among populations with a high chance of its occurrence in our country.

Copyright © 2020, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

1. Context

Occult hepatitis B virus (HBV) infection is characterized by the detection of a low level of HBV DNA in the liver or serum of people who are seronegative for HBV surface antigen (HBsAg) in a period other than the window period of acute infection (1, 2). Occult HBV infection (OBI) has been proposed to occur in several clinical contexts such as the recovery of the past infection characterized by the presence of antibodies to HBsAg (anti-HBs); chronic HBV carriage with very low, undetectable HBsAg levels and the presence of anti-hepatitis B core antigen (anti-HBc) as the only serum marker (isolated anti-HBc) or without any serum marker of HBV (seronegative); and chronic hepatitis B with surface gene escape mutations (3).

Some significant clinical concerns have been suggested for OBI, including (1) The probability of HBV transmission through blood transfusion or organ transplantation (4, 5); (2) chronic liver disease progression toward cirrhosis due to persistent inflammatory necrosis (6); (3) hepatocellular carcinoma (HCC) development due to the direct oncogenicity effect of HBV and/or the formation of necrotic inflammation following persistent replication of the virus (7); and (4) The possibility of HBV reactivation in immunosuppression conditions such as receiving chemotherapy or other immunotherapy (8).

The prevalence rate of OBI has ranged from zero to 63% among different populations studied in various provinces of Iran. This diversity has been observed among different groups in one region, as well as among a specific group from different areas of the country. For instance, the OBI prevalence in Tehran province in the north of Iran varied from zero among blood donors (BDs) (9) and multi-transfused patients (MTPs) (10) to 18% in HIV-positive individuals (11), 20% in HCV-positive patients (12), and 22% among people who inject drugs (PWID) (13). On the other hand, some studies found no OBI cases among Iranian BDs in provinces such as Tehran (9), Razavi Khorasan (14), Khuzestan (15), Kermanshah (15, 16), and Yazd (17) and some surveys reported the high rates among BDs in Isfahan (11.6%) (18), Fars (15.8%) (19), and Kerman (16.2 %) provinces (20).

This systematic review and meta-analysis study was performed to characterize the OBI epidemiology in Iran and estimate the pooled prevalence among different low- and high-risk Iranian populations such as BDs, hemodialysis (HD) patients, and HIV- and HCV-positive patients. The results of our review would help health authorities to make appropriate decisions for control of OBI in Iran, especially among high-risk groups.

2. Methods

2.1. Data Sources and Search Strategies

This systematic review and meta-analysis study was conducted following the PRISMA 2009 statement. The main purpose of the investigation was the presence of HBV DNA identified by polymerase chain reaction (PCR) in the blood samples of different population groups in Iran. Indexing phrases included “Iran” and all terms that referred to occult HBV infection everywhere in the text (OBI OR “Occult Hepatitis B” OR “Occult HBV” OR “HBsAg negative” OR “HBs Antigen negative”). Language equivalents of these words were used to search the documents published in Persian sources. Some international electronic resources such as ISI, PubMed, Scopus, ScienceDirect, and Proquest, as well as four Iranian databases including Scientific Information Database (SID), Barakat Knowledge Network System (previously named as IranMedex), Iranian Database of Publication (Magiran), and the Regional Information Centre for Science and Technology (RICeST), were searched until the end of 2018. Furthermore, all references identified from bibliographies of relevant review articles were manually searched. Iranian databases were explored for gray literature such as research projects, dissertations, theses, and abstracts. Besides, some available pertinent abstract booklets and conference proceedings were manually reviewed.

2.2. Study Selection and Data Extraction

After reviewing the titles and abstracts, all records that reported the prevalence of OBI among healthy individuals or different patient groups of Iran were chosen to review their full texts. Variables such as the first author, year of publication, year of study, study location, study population, sampling method, the number of cases with HBsAg and HBV DNA seropositivity, anti-HBc test results, and diagnostic methods used to assess the serum HBV genome were extracted from each study. The main inclusion criteria were the assessment of the HBV genome among at least 30 HBsAg seronegative samples selected through random or non-random sampling methods in a cross-sectional survey. Laboratory methods included Enzyme-Linked Immunosorbent Assay (ELISA) or chemiluminescence immunoassay to screen serum HBsAg and PCR techniques to detect serum HBV DNA. Surveys that evaluated HBV DNA in peripheral blood mononuclear cells or liver tissue samples were excluded. Besides, case reports, review articles, editorials, or letters with no report of OBI prevalence in a specific population were not included. The quality of studies was independently evaluated by two investigators, and eligible studies were selected based on their agreement.

2.3. Data Analysis

Data were analyzed using comprehensive meta-analysis software Ver. 3.3.070 (Biostat, Englewood, NJ, USA). Binomial distribution was used to calculate the prevalence in each study. The number of cases with detectable HBV DNA and the total number of studied samples were entered to calculate the event rate and its 95% confidence interval (CI). If a study referred to the event rate but did not provide the number of positive cases, it was recalculated through multiplying the total number of samples by the reported rate of OBI frequency in percentage. A weight was assigned to each study as the inverse variance. Using the Der-Simonian and Laird method, a random-effect model was applied when heterogeneity between studies was identified based on Cochran’s Q-test (P < 0.05) and I-square (I2) statistics (values of > 50%). The point prevalence rates and their 95% CIs for different populations were illustrated by forest plots.

Subgroup analyses were performed to explore the possible factors associated with heterogeneity. A meta-analysis was also implemented after removing surveys with most influences on the heterogeneity due to the reporting of a very high prevalence rate among a specific population. Moreover, additional analysis was done after excluding studies assessing the OBI rate among only cases with anti-HBc seropositivity. Furthermore, a meta-regression analysis was used to investigate significant changes in the prevalence rates over time. All statistical data were considered significant if a P value was less than 0.05.

3. Results

In the initial search of 254 citations retrieved from international electronic sources and 158 citations found in Iranian databases, 205 non-duplicated documents were selected, of which 90 surveys determined the prevalence of OBI in the Iranian population (Figure 1). The search for gray literature added 31 non-duplicate pertinent citations. After removing 38 overlapping surveys (the same studied population, sample sizes, methods, and findings), 83 non-duplicated and non-overlapping surveys were evaluated. A total of 55 non-duplicate and non-overlapping documents met the inclusion criteria and were used in the analysis (Table 1) (9-63). They reported OBI prevalence among 14,485 individuals (min: 31, max: 5000) from 16 provinces of Iran during 2004 - 2018 (Table 1). The studied population included healthy populations such as BDs, tissue donors, and healthcare personnel, as well as high-risk groups including thalassemia, hemophilia, and HD patients, HCV and/or HIV-positive individuals, PWID, patients with unknown liver disease, and family members of HBsAg-positive cases. All studies applied a PCR technique to detect OBI, comprising conventional PCR (20 studies), nested PCR (15 studies), and real-time PCR (20 studies).

Document search and selection for systematic review and meta-analysis of occult hepatitis B prevalence in Iran
Figure 1. Document search and selection for systematic review and meta-analysis of occult hepatitis B prevalence in Iran
Table 1. Selected Studies for Systematic Review and Meta-Analysis of Occult Hepatitis B Prevalence in Irana
StudyDate (Years)ProvincePopulationSample SizeHBV SerologyHBV DNA Detection MethodOBI
ConductionPublication
Ghaziasadi et al. (21)Un2017MarkaziGP (Children)558HBsAg-Real-time PCR54 (9.68)
Azarkar et al. (22)2016 - 20182019South KhorasanGP596Isolated anti-HBc+Nested PCR61 (10.23)
Karimi et al. (15)20132016Kermanshah/KhuzestanBDs2031HBsAg-Real time PCR0 (0)
Abbasi et al. (16)20132016KhuzestanBDs184HBsAg-Nested PCR0 (0)
Ahmadi Ghezeldasht et al. (14)20182018Razavi KhorasanBDs545HBsAg-Real-time PCR0 (0)
Shahabi et al. (23)Un2009Razavi KhorasanBDs60HBsAg-anti-HBc+Nested PCR0 (0)
Amini Kafi-abad et al. (9)Un2007TehranBDs230HBsAg-anti-HBc+Conventional PCR0 (0)
Vaziri and Javadzadeh Shahshahani (17)20152017YazdBDs74HBsAg-anti-HBc+Conventional PCR0 (0)
Alizadeh and Milani (24)2008 - 20092014TehranBDs5000HBsAg-Real-time PCR2 (0.04)
Khamesipour et al. (25)Un2011GuilanBDs78HBsAg-anti-HBc+Real-time PCR1 (1.28)
Pourazar et al. (18)Un2005IsfahanBDs43HBsAg-anti-HBc+Conventional PCR5 (11.63)
Behzad-Behbahani et al. (26)2001 - 20022006FarsBDs131HBsAg-anti-HBc+Conventional PCR16 (12.21)
Behzad-Behbahani et al. (19)Un2011FarsBDs76HBsAg-anti-HBc+Real-time PCR12 (15.79)
Kazemi Arababadi et al. (20)20082009KermanBDs352HBsAg-anti-HBc+Conventional PCR57 (16.19)
Vaezjalali et al. (27)20112013TehranBDs80HBsAg-anti-HBc+Nested PCR40 (50.00)
Samiee et al. (28)2014 - 20162018TehranCornea donors90HBsAg-anti-HBc+Real-time PCR11 (12.22)
Ahmad Akhoundi et al. (29)20112015TehranHCWs (Dental)52HBsAg-anti-HBc+Real-time PCR1 (1.92)
Borzooy et al. (30)Un2015TehranHealthy HCWs120HBsAg-Real-time PCR4 (3.33)
Abbasi et al. (31)Un2012GolestanHD patients100HBsAg-Conventional PCR0 (0)
Joukar et al. (32)20092012GuilanHD patients (59 HCV + cases)507HBsAg-Conventional PCR0 (0)
Kazemi Arababadi et al. (33)Un2009KermanHD patients (30 HCV + cases)90HBsAg-Conventional PCR0 (0)
Attarpour Yazdi (35)Un2016TehranHD patients (19 HCV + cases)45HBsAg-Conventional PCR0 (0)
Attarpour Yazdi (34)Un2017YazdHD HCV + patients34HBsAg-Conventional PCR0 (0)
Ranjbar et al. (63)20112017TehranHD patients200HBsAg-Real time PCR1 (0.50)
Ramezani et al. (36)2013 - 20142015TehranHD patients100HBsAg-Real time PCR1 (1.00)
Rastegarvand et al. (37)20122015KhuzestanHD patients203HBsAg-Nested PCR6 (2.96)
Haghazali et al. (38)20072011QazvinHD patients (10 HCV+ cases)129HBsAg-Conventional PCR5 (3.88)
Keyvani et al. (39)2007201314 provincesHD patients103Isolated anti-HBc+Conventional PCR5 (4.85)
Ziyaeyan et al. (40)Un2011FarsHD patients55HBsAg-Real time PCR4 (7.27)
Hashemi et al. (41)2011 - 20122015KhuzestanRelatives of HD patients82HBsAg-Nested PCR0 (0)
HD patients82HBsAg-9 (10.98)
Ziaee et al. (42)Un2017South KhorasanHemophilia86HBsAg-Nested PCR8 (9.30)
Kazemi Arababadi et al. (43)2006 - 20072008KermanThalassemia (27 HCV+ cases)60HBsAg-Conventional PCR0 (0)
Makvandi et al. (44)2011 - 20122014KhuzestanPatients with Elevated ALT120HBsAg-Nested PCR12 (10.00)
Kaviani et al. (45)1997 - 20012006FarsPatients with Cryptogenic hepatitis104HBsAg-Conventional PCR2 (1.92)
Hashemi et al. (46)2011 - 20122015KhuzestanPatients with Cryptogenic cirrhosis50HBsAg-Nested PCR7 (14.00)
Sharifi-Mood et al. (47)2005 - 20062009Siatan & BaluchestanFamily members of HBsAg + cases110Isolated anti-HBc+Conventional PCR3 (2.73)
Shahmoradi et al. (48)Un2012MazandaranChildren born to HBsAg + mothers75HBsAg-Real-time PCR/Nested PCR21 (28.00)
Ayatollahi et al. (49)20162019YazdPatients with cured HBV infection96HBsAg-Real-time PCR28 (29.17)
Shavakhi (50)2003 - 20042004TehranHCV + patients31HBsAg-Conventional PCR0 (0)
Jonaidi-Jafari et al. (10)2009 - 20102017TehranHCV + Thalassemia and hemophilia patients145HBsAg-Conventional PCR0 (4.85)
Eshraghi-Mosaabadi et al. (51)2013 - 20142018TehranHCV + PWID94HBsAg-Nested PCR7 (7.45)
Zandieh et al. (52)Un2005TehranHCV + patients201HBsAg-Nested PCR17 (8.46)
Shavakhi et al. (53)2002 - 20042009TehranHCV + patients103HBsAg-Nested PCR20 (19.42)
Vakili Ghartavol et al. (12)2010 - 20112013TehranHCV + patients50HBsAg-Nested PCR10 (20.00)
Majzoobi et al. (54)2013 - 20142016HamadanHCV/HIV + patients48Isolated anti-HBc+Conventional PCR0 (0)
Zhand et al. (55)Un2015GolestanHIV + patients120HBsAg-anti-HBc+Conventional PCR0 (0)
Aghakhani et al. (56)20142016TehranHIV + patients (30 HCV + cases)92HBsAg-Real-time PCR2 (2.17)
Tajik et al. (57)2015 - 20172018TehranHIV + patients151HBsAg-Real-time PCR4 (2.65)
Janbakhsh et al. (58)Un2017KermanshahHIV + patients (37 HCV + cases)66HBsAg-anti-HBc+Real-time PCR8 (12.12)
Mohraz et al. (11)Un2016TehranHIV + patients (99 HCV + cases)172HBsAg-Real-time PCR31 (18.02)
Honarmand et al. (59)20122014FarsHIV + patients84HBsAg-Nested PCR53 (63.10)
Chenari et al. (60)2011 - 20132014Razavi KhorasanHTLV-1 + patients109HBsAg-Real-time PCR1 (0.92)
Asli et al. (13)2013 - 20142016TehranPWID59HBsAg-anti-HBc+Nested PCR13 (22.03)
Azizolahi et al. (61)20152017KhuzestanPatients with rheumatologic disorders134HBsAg-Real-time PCR1 (0.75)
Ghorbani Bejandi et al. (62)Un2016TehranPatients with Behcet's disease95HBsAg--7 (7.37)

Abbreviations: ALT, alanine transaminase; anti-HBc+, Seropositive for anti-hepatitis B core antigen; BDs, blood donors; HBsAg-, seronegative for hepatitis B virus surface antigen; HBsAg +, seropositive for hepatitis B virus surface antigen; HCWs, healthcare workers; HCV+, seropositive for hepatitis C virus; HD, hemodialysis patients; HIV+, seropositive for human immunodeficiency virus; GP, general population; PWID, people who inject drugs; Un: undetermined.

aValues are expressed as No. (%).

The rate of OBI prevalence considerably varied in different parts of the country with the highest prevalence (63.1%) reported among the HIV-positive population in Fars province (Table 1).

3.1. OBI Prevalence Among Blood Donors

A total of 13 surveys with a report of OBI prevalence among Iranian BDs were used in the meta-analysis. Nine studies investigated the presence of OBI only among HBsAg-negative, and anti-HBc-positive BDs, and four studies explored OBI among HBsAg-negative BDs, regardless of their anti-HBc test results. As Table 2 shows, the first group comprised 1,124 individuals from six provinces. The Cochrane Q-test showed heterogeneity between the studies (P < 0.001, I2 = 90.1%), and the rate of OBI prevalence was estimated at 8.81% (95% CI: 4.11 - 17.91%). After excluding one survey reporting an unexpectedly high rate of OBI (50.0%) (27), the value of I-square decreased to 74.3%, and the OBI rate declined to 7.90% (95% CI: 4.33 - 13.99%, Figure 2). Among the remaining eight surveys, the rate of OBI did not vary by the conventional, real-time, and nested PCR subgroups (P = 0.105, Table 2).

Forest plot of studies on occult hepatitis B infection prevalence among anti-HBc-positive Iranian blood donors
Figure 2. Forest plot of studies on occult hepatitis B infection prevalence among anti-HBc-positive Iranian blood donors
Table 2. The Pooled Estimates of Occult HBV Infection Prevalence Among Different Iranian Populations, According to the Result of Meta-Analysis
PopulationPrevalenceSample Size, Total (Min, Max)Pooled EstimateHeterogeneity TestI-Squared, %
Point, %95% CICochran’s QP Value
Blood donorsWith nine surveys included only anti-HBc-positive cases1124 (43, 352)8.814.11 - 17.9180.7< 0.00190.1
After removing one survey with a report of very high prevalence rate1044 (43, 352)7.904.33 - 13.9927.20.00374.3
Based on the PCR method used to detect HBV DNA
Conventional (five studies)830 (43, 352)8.313.75-17.4216.30.00375.8
Real-time (two studies)154 (76, 78)7.872.21 - 24.456.40.01184.5
Nested (one study)60 (60, 60)0.820.04 - 16.0801.00
Between subgroups---4.50.105-
With four studies investigating HBsAg-negative BDs regardless of their anti-HBc test results7760 (184, 5000)0.060.02 - 0.161.90.5880
Hemodialysis patientsWith all 12 related studies1648 (34, 507)2.491.28 - 4.8130.80.00164.2
After excluding one survey with only isolated anti-HBc cases1545 (34, 507)2.120.98 - 4.5430.60.00167.3
Based on the PCR method used to detect HBV DNA
Conventional (six studies)905 (34, 507)1.010.28 - 3.538.90.11343.9
Real-time (three studies)355 (55, 200)1.980.44 - 8.437.70.02174.0
Nested (two studies)285 (82, 203)5.581.29 - 22.756.60.01084.8
Between subgroups---7.40.024-
HCV-positive patientsWith all 14 related studies1029 (30, 201)7.764.57 - 12.8648.2< 0.00173.9
After eliminating two surveys with only anti-HBc positive cases944 (30, 201)7.324.10 - 12.7543.6< 0.00174.8
Based on the PCR method used to detect HBV DNA
Conventional (six studies)367 (30, 145)1.510.54 - 4.162.20.8240
Real-time (two studies)129 (30, 99)17.016.96 - 35.953.90.04874.4
Nested PCR (four studies)448 (50, 201)12.857.70 - 20.6711.90.00874.7
Between subgroups---25.9< 0.001-
With six studies with HCV RNA-positive patients561 (30, 201)8.774.01 - 18.1121.40.00176.8
HIV-positive patientsWith all seven related studies733 (48, 172)6.911.90 - 22.17116.3< 0.00194.8
After removing one survey with a report of very high prevalence rate649 (48, 172)4.441.56 - 12.0231.7< 0.00184.2
Based on PCR method used to detect HBV DNA
Conventional (two studies)168 (48, 120)0.650.06 - 6.540.20.6500
Real-time (four studies)481 (66, 172)6.952.57 - 17.4522.2< 0.00186.5
Between subgroups---9.30.002-
After removing three surveys with only anti-HBc positive cases499 (84, 172)11.782.24 - 43.7794.7< 0.00196.8

Abbreviations: CI, confidence interval; Max, maximum; Min, minimum.

The second group included 7,760 donors from four provinces. There was no heterogeneity between the studies (P = 0.588), and the rate of OBI prevalence was assessed as low as 0.06% (95% CI: 0.02 - 0.16%, Figure 3). A meta-regression analysis indicated no significant time trend in the OBI prevalence rate among both subpopulations of BDs (P = 0.967 and P = 0.510, respectively).

Forest plot of studies on occult hepatitis B infection prevalence among Iranian blood donors regardless of their anti-HBc test results
Figure 3. Forest plot of studies on occult hepatitis B infection prevalence among Iranian blood donors regardless of their anti-HBc test results

3.2. OBI Prevalence Among Hemodialysis Patients

Twelve surveys from eight provinces of Iran reported the rate of OBI among 1,648 HD patients. Based on heterogeneity found between the studies (P = 0.001, I2 = 64.2%), the prevalence rate was estimated to be 2.49% (95% CI: 1.28 - 4.81%, Figure 4). After excluding one survey assessing OBI among only patients with isolated anti-HBc (39), no significant change occurred in the value of I-square (67.3%) and OBI prevalence (2.12%; 95% CI: 0.98 - 4.54%). As Table 2 indicates, the rate of OBI was higher in the nested PCR subgroup (5.58% [95% CI: 1.29 - 22.75%]) than in the real-time and conventional PCR subgroups (1.98% [95% CI: 0.44 - 8.43%] and 1.01% [95% CI: 0.28 - 3.53%], respectively, P = 0.024). In addition, no significant change over the years was found in the OBI prevalence among Iranian HD patients (P = 0.946).

Forest plot of studies on occult hepatitis B infection prevalence among Iranian hemodialysis patients
Figure 4. Forest plot of studies on occult hepatitis B infection prevalence among Iranian hemodialysis patients

3.3. OBI Prevalence Among HCV-Positive Patients

A total of 14 surveys from six provinces of Iran reported the OBI prevalence among 1,029 anti-HCV-positive patients. Considering heterogeneity found between the studies (P < 0.001, I2 = 73.9%), the rate of OBI prevalence was estimated at 7.76% (95% CI: 4.57 - 12.86%) (Figure 5). Based on the meta-analysis of only six studies that reported occult infection among 561 anti-HCV- and HCV RNA-positive patients, the OBI prevalence was estimated to be 8.77% (95% CI: 4.01 - 18.11%) (Table 2). After excluding two surveys assessing OBI among only anti-HBc-positive patients (54, 58), no change was observed in both I-square (74.8%) and OBI frequency (7.32%; 95% CI: 4.10 - 12.75%). Among the remaining 12 studies, a subgroup analysis was done to assess the modulating effect of three different methods used to detect serum HBV DNA, including conventional, nested, and real-time PCR (Table 2). The rates of OBI were apparently higher in real-time and nested PCR subgroups (17.01% [95% CI: 6.96 - 35.95%] and 12.85% [95% CI: 7.70 - 20.67%], respectively) than in conventional PCR subgroup (1.51% [95% CI: 0.54 - 4.16%], P < 0.001). Besides, no significant relationship was detected between the year of the study and the OBI prevalence rate among Iranian HCV-positive patients (P = 0.058).

Forest plot of studies on occult hepatitis B infection prevalence among Iranian HCV-positive patients
Figure 5. Forest plot of studies on occult hepatitis B infection prevalence among Iranian HCV-positive patients

3.4. OBI Prevalence Among HIV-Positive People

Regarding the OBI prevalence among the Iranian population with HIV infection, seven surveys reported the rate among 733 HIV-positive cases from five provinces. Based on heterogeneity detected between the studies (P < 0.001, I2 = 94.8%), the OBI frequency was estimated at 6.91% (95% CI: 1.90 - 22.17%). After excluding one survey that reported an unexpectedly high rate of OBI (63.1%) (59), the value of I-square was declined to 84.2%, and the OBI rate decreased to 4.44% (95% CI: 1.56 - 12.02%) (Figure 6). A subgroup analysis was applied to the remaining six surveys regarding the different molecular methods used to diagnose serum HBV DNA (Table 2). The rate of OBI was significantly higher in the real-time PCR subgroup (6.95% [95% CI: 2.57 - 17.45%]) than in the conventional PCR subgroup (0.65% [95% CI: 0.06 - 6.54%], P = 0.002). After removing three studies that evaluated OBI among only the cases with anti-HBc seropositivity (54, 55, 58), the data from the other four surveys were analyzed. With no change in the value of I-square (96.8%), the rate of OBI prevalence increased to 11.78% (95% CI: 2.24 - 43.77%). A meta-regression analysis showed no significant time trend in the OBI prevalence rate among Iranian HIV-positive individuals (P = 0.599).

Forest plot of studies on occult hepatitis B infection prevalence among Iranian HIV-positive individuals
Figure 6. Forest plot of studies on occult hepatitis B infection prevalence among Iranian HIV-positive individuals

3.5. OBI Prevalence Among Other Groups

As shown in Table 1, the rate of OBI prevalence has been reported as about 10% in both children and adults from the general Iranian population (21, 22). Likewise, one study among cornea donors in Tehran indicated that 12.2% had molecular evidence of occult infection in their sera (28). The prevalence rate of OBI among PWID ranged from 7.4% to 22% in Tehran (11, 13, 51) while it was as high as 17.9% among this population from Kermanshah (58). Regarding OBI among MTPs, one survey found no cases of OBI among thalassemia patients (43), but another study reported a rate of 9.3% among hemophilia patients (42). Similarly, one survey detected only two cases of OBI among 104 patients with non-cirrhotic cryptogenic hepatitis (45); however, another survey reported a rate of 14% among patients with cryptogenic cirrhosis (46). A considerably high frequency of OBI (28%) was observed among children born to HbsAg-positive mothers (48). In another study, HBV DNA was detected in the serum of 29.2% of individuals with a history of chronic HBV infection who experienced HBsAg seroconversion (49). Moreover, 2-3% of healthcare personnel in Tehran had OBI (29, 30).

4. Discussion

The prevalence of OBI in each population depends partly on the studied people, the prevalence of HBV infection and its risk factors in the community, as well as the sensitivity of techniques used for the detection of serum HBsAg and DNA (64-66). In countries with high endemicity of HBV infection, where the majority of infections occur perinatally or during early childhood, a higher percentage of affected adults might have chronic HBV infection while they are not seroreactive for HBsAg (67). In two systematic reviews of studies conducted in 25 years from 1990 to 2014 (68, 69), the overall rates of HBV infection among the general population of Iran were estimated at 2.2% to 3%, ranging from 0.7% and 0.9% in Kermanshah and Kurdistan provinces, respectively, to 8.9% in Golestan Province. Therefore, Iran could be considered a country with a low-intermediate level of HBV infection. The current systematic review showed a significant variation in the OBI prevalence reported from different provinces of Iran, as well as among diverse populations in the same province. In a study by Azarkar et al. (22), 596 out of 5,234 people selected from the general population of Birjand, South Khorasan, were seroreactive for anti-HBc, of whom 10.2% were detected to be seropositive for HBV DNA. In addition, Ghaziasadi et al. (70) showed that 9.7% of HBsAg- and anti-HBc-negative children in Alborz, Markazi Province, were HBV DNA positive.

Today, OBI is the leading cause of HBV infection following blood transfusion in countries with both low and high levels of HBV endemicity (71). The prevalence of OBI among HbsAg-negative blood donors depends on the level of HBV infection in the community, as well as the serological or molecular methods used to screen the virus (6, 72). The OBI frequency has been reported in 0.1 to 2.4% of HbsAg-negative and anti-HBc-positive blood donor volunteers in western communities with a 5% rate of previous HBV exposure. On the other hand, up to 6% of the donors in HBV-endemic areas, where 70% to 90% of the population show evidence of HBV exposure, are OBI-positive (73). In the present meta-analysis, the prevalence of OBI was estimated at 8.81% (95% CI: 4.11 - 17.91%) among anti-HBc-positive BDs of Iran; however, it was assessed as low as 0.06% (95% CI: 0.02-0.16%) among BDs regardless of their serum anti-HBc status. The detection rate of serum HBV DNA among Iranian HbsAg-negative blood donors varied from 0.15% in Tehran (9) to 2.72% in Zahedan (47). This variation can be partly explained by different prevalence rates of overt HBV infection among BDs from different parts of Iran. In a systematic review of studies with at least 1,000 samples during 2000 - 2015 (74), the overall frequency of HBsAg seropositivity in Iranian blood donors was estimated to be 0.6% (95% CI: 0.4 - 0.8%); however, the prevalence varied from 0.11% in Chaharmahal and Bakhtiari Province to 2.4% in Golestan Province.

Studies showed that occult hepatitis B is mainly found among populations at risk of HBV infection and those with liver disease (2, 6). Similarly, the prevalence of HBsAg seropositivity is reported to be high among high-risk populations of Iran. A review of studies published from 2003 to 2015 (75) estimated the average prevalence rate of 4.8% for HBV infection among drug abusers, PWID, prisoners, and prostitutes in Iran, with the highest prevalence (24.7%) among PWID in Tehran. The HD patients are at risk of acquisition of parenterally transmitted infections. A review of studies published during 1985 - 2015 showed that up to 40% of Iranian HD patients were suffering from HBV infection with an average prevalence of 4% (76). The repetitive blood transfusions, repeated invasive procedures, low response to HBV vaccination, and immunosuppression status are proposed as the reasons for a high incidence of hepatitis B in these patients (77, 78). Moreover, chronic HCV infection in some HD patients may complicate the condition (79). Consistently, the prevalence of OBI has been reported to be up to 36% in HD patients and up to 10% in patients with continuous peritoneal dialysis (6, 77). In 1997, Cabrerizo et al. (80) found HBV DNA in 58% of sera samples and 54% of peripheral blood mononuclear cells derived from 33 HbsAg-negative HD patients. The researchers concluded that the absence of HBsAg in dialysis patients could be due to the presence of HBV surface antigen-antibody immune complex or mutations in the S gene of HBV that precluded HBsAg from being identified by conventional methods. The prevalence of OBI in HD patients varies from country to country in the Middle East. It is reported as 4.1% in Egypt (81). In a study from Turkey (82), OBI was reported in 12 out of 33 HD patients with chronic HCV; however, in other dialysis units from this country, the results were negative (83). Based on the current meta-analysis, the prevalence of OBI among HD patients of Iran was estimated at 2.49% (95% CI: 1.28 - 4.81%) with the highest rate (11%) in patients from Khuzestan Province.

There are significant reports that OBI is more common in people with chronic liver disease, especially those with chronic HCV infection (2, 66, 84). The presence of OBI in patients with chronic hepatitis C has been repeatedly reported and the possible role of OBI in the progression of liver damage following HCV infection has been discussed (78). Cacciola et al. (85) detected the HBV genome in the liver tissue of 33% of patients with HCV infection compared to 14% of HCV-negative groups. In a review, Brechot et al. (64) concluded that HBV DNA was detectable by the PCR technique among 20% - 30% of serum samples of anti-HCV-positive patients and 40% - 50% of liver samples. In the present meta-analysis, the prevalence of OBI among Iranian HCV-positive patients was predicted as 7.76% (95% CI: 4.57 - 12.86%). As hepatitis B and C are common infections with the same transmission routes and risk factors, it is expected that a substantially high prevalence of OBI is reported among patients with chronic hepatitis C (86, 87). Moreover, OBI has shown to worsen the clinical course of HCV infection. Indeed, there is a higher degree of inflammatory activity and fibrosis and a greater rate of cirrhosis and HCC in HCV patients with OBI (88, 89). This clinical consequence of OBI is likely due to the integration of HBV into the host genome or the production of pro-oncogenic proteins by the HBV-free genome within the liver (90). Cacciola et al. (85) reported that 33% of patients with HCV infection and OBI were cirrhotic compared to 19% of those patients with no evidence of occult infection. In addition, it is reported that occult hepatitis B may lead to increased HCV RNA load and serum transaminases levels (90).

Due to similar transmission routes and risk factors, HBV/HIV co-infection is a common condition. Several studies indicated a higher prevalence of HBsAg seropositivity among HIV-positive patients than among HIV-negative individuals (91, 92). The current investigations showed different rates of OBI in HIV-positive groups ranging from zero to 89%; however, the prevalence remains controversial (6, 93, 94). In our systematic review, the prevalence of OBI in HIV-positive patients was estimated to be 6.91% (95% CI: 1.90 - 22.17%); however, a lower rate (4.44%, 95% CI: 1.56 - 12.02%) was discovered after excluding one survey with a high rate of OBI. Some researchers believe that the reasons for diversity observed in OBI prevalence among HIV-positive patients are the same as seen in HIV-negative individuals. These include the different incidence and risk factors of HBV infection in the general population, as well as various methods applied to measure serum HBsAg and/or HBV DNA (6, 94). However, differences between reports may also be explained by fluctuations in HBV proliferation over time, the coincidence of HCV infection, or the impacts of therapeutic strategies for both HIV and HBV. Additionally, heterogeneity between the study populations and regional differences in the overall prevalence of HBV infection may contribute to the observed variance in the prevalence of OBI. HIV patients with OBI might have lower CD4 counts and high plasma HIV RNA loads (93). Reactivation of occult infection and HBsAg seroconversion could also occur with immunosuppression conditions. Thus, the clinical importance of OBI in HIV-positive individuals should be emphasized (90).

5. Limitation

In this review, we tried to address the heterogeneity between studies among different populations through excluding studies with high impacts on the prevalence rates and performing subgroup analysis, as well as meta-regression methods. However, other sources of heterogeneity were impossible to discover.

6. Conclusions

This review estimated the high rates of OBI frequency among high-risk populations of Iran. It is strongly suggested that occult hepatitis B be investigated among Iranian populations with a high chance of its occurrences such as dialysis patients, HCV-positive patients, and HIV-infected individuals.

Footnotes

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