Background
Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) are both major public health problems worldwide. They share similar routes of transmission, namely through blood and blood products, sharing of needles to inject drugs, and sexual activity, resulting in coinfection with the two viruses a common event[
1]. Studies reported that coinfection with HBV was a well-documented cause of liver-related complications in individuals with HIV infection and is associated with an increased risk of mortality[
2‐
4]. Because of the significant burden and clinical impact of HBV in HIV-infected individuals, understanding the epidemiologic characteristics of HBV infection in HIV-infected populations is crucial. It has been estimated that HBV accounts for 400 million chronic infections worldwide. The prevalence of HBV infection among HIV-infected persons varies markedly, from 5% to 30% in different regions of the world[
5]. HBV infection is highly endemic in China, with 5.84% prevalence of HBV surface antigen (HBsAg) in the population of 1–59 years of age in 2007[
6]. However, data on the prevalence of HBV coinfection in HIV infected adults in China remains limited[
7,
8].
HBV has ten genotypes (A through J) with wide geographic distribution. Genotypes B and C are most common in Asia, and genotype A, which is more responsive to interferon therapy than are the other genotypes, is most common in Northern and Central Europe[
9]. However, the role of HBV genotypes in the natural history of the infection and in the response to therapy in patients with HIV coinfection is unclear. In China, the most common genotypes of HBV in individuals who have HBV infection alone are C and B[
10]. However, data on the HBV genotype distribution in HIV/HBV co-infected Chinese individuals still remains limited.
Because of the different clinical characteristics of HIV infected patients and blood donors, the epidemiological characteristics of HBV in the two HIV infected groups may differ from each other, which could be significant for therapy and prevention of HBV in HIV infected adults.
Sichuan is a southwest province in China with a total population of about 89 million. The prevalence of HIV in Sichuan is higher than that in many other provinces and ranks in the top five provinces of highest prevalence in China. Therefore, in this study we investigated the prevalence of HBV in newly diagnosed HIV-infected blood donors and AIDS patients in Sichuan, China and analyzed the HBV genotype distribution, viral loads, serological markers of HBV and their relationships.
Discussion
Coinfection of HBV with HIV complicates the clinical course, management and may also adversely affect therapy for HIV infection. Treatment of patients with HIV/AIDS coinfected with HBV is even more complex[
14,
15]. Thus it is important to determine whether patients with HIV/AIDS are coinfected with HBV. All over the world, increasing attention has focused on HIV coinfection with HBV in recent years[
5] and several studies have reported the HIV/HBV prevalence in China[
7,
8]. However, most of the studies just adopted seroepidemiological survey methods to detect HBsAg to initially assess the status of HBV infections in HIV/AIDS populations in China, which may underestimate the actual prevalence of HBV for many reasons including window period infection, HBsAg detecting negative for mutations in S region and occult HBV infection. In this study we conducted both HBsAg and HBV DNA detection to assess the HBV prevalence in HIV infected populations and got a result of 12.9% which was higher than the HBV prevalence in the Chinese general population[
6]. In addition, the data we got suggests higher HIV/HBV prevalence in Chinese populations than reported by other studies[
7,
8]. One reason may be that HBV DNA detection was conducted and some HBsAg negative HBV DNA positive subjects were found in this study. In addition, HBV and HIV sole prevalence in the general population in different regions may affect the prevalence of HIV/HBV coinfection determined in different researches and both HBV and HIV are more endemic in Sichuan, the region we studied, than many other provinces in China. The HBV/HIV coinfection prevalence of 12.9% in the present study is significant and confirms that HBV is a major threat to HIV infected individuals in China, as reported in other parts of the world[
5]. In our study, the HBV coinfection prevalence was determined separately in HIV infected blood donors and AIDS patients and the result showed that the HBV prevalence in the former group was significantly lower than that in the latter group, which may be due to that the HBV prevalence in Chinese blood donors was lower than that in the general Chinese people.
In this study, more HBeAg negative individuals were found in the HBsAg positive donors than in the patients and the average HBV DNA levels were determined lower in donors than in patients, which may explain why most of the HBV/HIV infected blood donors are asymptomatic. In addition, in this study, 10% of the HBeAg-negative patents had an undetectable HBV DNA, and an additional 38.3% had a HBV DNA level less than 2000 IU/ml, which is the level above which treatment for HBV infection is considered. In contrast, all of the HBeAg-positive subjects had detectable HBV DNA levels that were more than 10
5 IU/ml. In the Nigerian study, these low levels were also found primarily in HBeAg-negative patients and these findings are supported by the multivariable analysis by other studies demonstrating that HBeAg-positive status was the only factor associated with higher HBV DNA levels[
16]. Thus, it is possible to detect HBeAg to determine if HBV treatment needs to be started in HIV infected individuals when HBV DNA assays are not available in resource-limited settings.
Genotypes C and B were the major HBV genotypes endemic in Mainland China in the individuals with HBV infection alone and genotype C is more prevalent than genotype B in general populations in Sichuan province[
10]. In this study, we found the most prevalent genotype was B and followed by genotype A and C in the HBV/HIV coinfected individuals, which was quite different from the genotype distribution in the population with HBV infection alone. This may explain the high rate of HBeAg negative individuals in the HBV/HIV coinfected populations detected in this study in that genotype B HBV is less virulent than genotype C and genotype B has a higher rate of seroconversion from HBeAg to anti-HBe. If the HBV genotype distribution demonstrated in our study is the fact, it’s good news for HBV/HIV coinfected populations. However, there is still one question. It is known that HIV infection would impair the cell mediated responses and enhances the kinetics of HBV replication, thus, genotype C HBV, which has greater capability to replicate, is considered to be more likely to infect the HIV infected individuals. This seems to be contradictive with HBV genotype distribution determined in our study. Thus, more studies are needed to determine the HBV genotype distribution in the HBV/HIV coinfected individuals and its mechanism needs to be analyzed in the future.
Through HBV DNA detection, 6 HBsAg positive but HBV DNA negative subjects were found in our study. It seems to be very rare to find HBsAg in the absence of HBV DNA which may be due to high sensitivity of HBV DNA test by nested-PCR used in this study. However, the existence of HBsAg+/HBV DNA- samples suggested that the HBV DNA testing can’t substitute the testing of HBsAg in blood donation screening. In addition, 4 HBV DNA positive but HBsAg negative subjects were found. A number of explanations for the positivity of HBV DNA in HBsAg negative samples have been proposed, including window period infection, occult HBV infection (OBI), genetic variations in the S gene and the presence of immune complexes in which HBsAg may be hidden[
17]. To analyze the cause of HBsAg negative, we analyzed the sequence of S gene of the four samples and found three mutations in two subjects. All of the three mutations were located in the sequence coding the central major hydrophilic region (MHR) from residues 103–173 which was exposed at the surface of viral particles and may be related to the failure of HBsAg detection. In the 4 subjects, subject 1 was found with G145R mutation, which was reported as the most important and best-documented mutation in MHR and was reported as the most critical substitution to prevent HBsAg detection. In addition, subject 1 was found positive for HBeAg and with high viral load. Thus, Sample 1, very much likely, was a failure in HBsAg detection due to the outdated quality of the method used, which manufacturer has not yet taken care to assess its performance for detecting HBsAg mutants. It’s perfectly known at present that appropriate modifications in assay design improve such performance if implemented, including a significant improvement of the ability to detect samples containing G145R mutants[
18,
19]. Therefore, the methods used for testing HBsAg should be carefully selected for avoiding such diagnostic mistakes. Occult HBV infection (OBI) is characterized by positive HBV-DNA in serum (and/or hepatic tissues) of individuals negative for serum HBsAg. A study in Germany showed that the occult HBV infection rate in patients with HIV/AIDS was 2.9%[
20]. Although occult hepatitis B infection alone may not have clinical consequences, it may become injurious when the virus is reactivated after immunosuppression, which suggests that HIV coinfection is a high risk for OBI[
21,
22]. According to the serological markers testing results and HBV DNA load, subject 3 can be determined as OBI. Subjects 2 and 4 were detected positive for only anti-HBc but not for the other four serological markers. Thus, it’s difficult to determine them as OBI unless anti-HBc IgM testing would be done to exclude that they were during the seroconversion phase of the acute HBV infection.
The current study had some limitations. Firstly, the sample size was relatively small and it was a single time point testing without any follow-up. Secondly, Since it was a cross-sectional study, liver disease characteristics such as alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels and HIV disease characteristics including CD4+ T-cell counts and HIV RNA levels were not determined in this study and we could not comment on the clinical significance of HBV in HIV infected populations included in our study. Thirdly, the data of HIV acquired route of the subjects were not collected, thus it’s impossible for us to analyze the impact of HIV transmission mode on HBV coinfection. Lastly, a control group of HIV negative was not included in the study and we could not compare the HBV infection in the HIV positive group with the negative group. However, some data about the HBV infection in general Chinese people were used to do the comparison.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
MH and ZL were responsible for conceptualizing the study. JW critically reviewed and revised the manuscript. YL and PZ analyzed the data and drafted the manuscript. The other authors were responsible for the detection of the samples. All the authors read and approved the manuscript.