Hepatitis D virus (HDV) is a peculiar, small, defective virus that requires the assistance of hepatitis B virus (HBV) surface antigen (HBsAg) for replication and pathogenesis [1]. Accordingly, HDV infection can occur via either coinfection with HBV or superinfection in patients with chronic hepatitis B. The main transmission routes of HDV are parenteral and sexual contact. In addition, mother-to-child transmission can occur [2]. Despite being a defective virus, HDV infection is widely perceived as the most severe and aggressive form of human viral hepatitis. Approximately 10% to 15% of patients with hepatitis D progress to cirrhosis within 1 year to 2 years, and 70% to 80% of patients progress to cirrhosis within 5 years to 10 years [3]. Moreover, HDV infection is more prone to hepatic decompensation and is associated with a higher risk of hepatocellular carcinoma [4]. However, HDV infection has been considered a relatively rare disease over the past decades as a result of the universal promotion of HBV vaccination and the clinical neglect of HDV detection. According to recent meta-analyses, the approximate HDV infection rate is 4.5% to 14.57% in the HBsAg-positive population, affecting up to nearly 72 million individuals worldwide [5,6].

Given the shared transmission routes with HIV, HIV/HBV/HDV triple infection is relatively common [7]. HIV/HBV/HDV triple infection is not only widespread but also associated with worse outcomes than monoinfection. First, it can have a negative impact on disease progression for people living with HIV. Combination with hepatitis virus infection may promote immune activation, causing dysfunction of CD4⁺ and CD8⁺ T lymphocytes and natural killer cells, resulting in poor immune recovery after antiretroviral therapy, thus affecting AIDS disease progression [8,9]. Additionally, HIV combined with HBV or HDV infection significantly reduces the clearance rate of these 2 types of hepatitis virus and prolongs the course of hepatitis [10]. Meanwhile, liver fibrosis is significantly accelerated after coinfection, and patients are also at higher risk of mortality due to liver cirrhosis, hepatic decompensation, hepatocellular carcinoma, and other liver diseases [11,12]. Significantly higher rates of poorer prognosis also occur. Thus, the disease burden of HIV/HBV/HDV triple infection appears more serious than initially expected.

There have been several meta-analyses exploring the global HIV/HBV coinfection rate; however, the prevalence of HIV/HBV/HDV triple infection remains largely unknown. Chu et al [13] examined the prevalence of multiple hepatitis viruses and HIV infection among drug users in Taiwan and found that HIV/HBV/HDV infection rates were as high as 16.7% among HIV-positive drug users. Shen et al [14] pooled the HIV/HBV/HDV triple infection rate in the global population from 2002 to 2018 and estimated a triple infection rate of only 1.03% in people living with HIV. In addition, Nicolini et al [15], in 2015, tested triple infection in blood samples from the Italian general population and found a triple infection rate of 3.5%. In general, the results of current studies on HIV/HBV/HDV triple infection rates fluctuate widely, and some studies may underestimate triple infection rates to some extent due to the small number of included samples or limitations of the included population characteristics [14]. This systematic review and meta-analysis aimed to determine a high reliability estimate of the prevalence of HIV/HBV/HDV triple infection in people with HBV infection or living with HIV globally.

This meta-analysis was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, and it was registered in PROSPERO (CRD42021273949).

Since the first discovery of the HDV in 1977 [29], it is estimated that 15 million to 20 million people have been infected worldwide [30,31]. Given that HDV is a defective virus dependent on the envelope proteins of HBV for assembly and release of infectious virus particles, HDV infection occurs either with or secondary to HBV infection. People infected with HDV can also have other viral infections, and chronic HDV infection is considered to be the most severe form of viral hepatitis infection in humans [32]. HIV was first reported in 1981, and the number of people living with HIV and deaths due to illness have remained high for a long time [33]. The virus is widely prevalent worldwide. As of 2018, there were more than 37.9 million people living with HIV in the world, and a total of 35 million people have died from AIDS-related diseases [34]. HIV infection causes progressive immunodeficiency, making people living with HIV highly susceptible to coinfection with other diseases. HBV and HDV are common viruses for coinfection in people living with HIV, as all 3 share the same route of infection [14,35]. Studies have shown that HIV coinfection with HBV and HDV is widespread in various regions of the world, but the coinfection rate varies among countries and regions [36]. HIV coinfection with HBV or HDV can cause more serious damage to the body than a single infection, and the harm of triple infection is even more serious. Therefore, it is of great public health significance to actively prevent such coinfections [37,38].

The results of this meta-analysis showed that the prevalence of HIV/HBV/HDV triple infection was 7.4%. The results of the subgroup analysis showed significant regional differences in global triple infection rates. The prevalence of triple infection is significantly higher in Asia, especially in Taiwan and China, than in other countries or regions. These results may be caused by several reasons. First, the included studies included people with IDU; IDU is a high-risk factor that may promote triple infections [39]. In addition, the higher prevalence rate might be due to the small sample size of the included studies, which may not accurately reflect the real situation of triple infection in this population. We found that the characteristics of the study population greatly influenced the prevalence; for example, the prevalence of triple infection in the Cameroon region was higher because the study population was HBsAg-positive and in a general hospital, which itself confers high risk for infection. Among the different sexes, the results of this meta-analysis showed a higher rate of triple infection in men than in women, which is consistent with several other studies [40,41]. This review suggested that men with HIV or HBV infection may have a higher prevalence of triple infection, and more attention should be given to the prognosis of their triple infection.

There were significant differences in the rate of triple infection for people living with HIV from different population sources, which was similar to rates for HIV/HBV coinfection [42]; however, for triple infection, men who have sex with men and people living with HIV are particularly worthy of attention. The rate of triple coinfection in this population reached 7.9%, exceeding the rate of triple infection in other populations. Nevertheless, the literature related to these special populations suffers from the same shortcomings as aforementioned, with small numbers, regional limitations, small sample sizes, and mostly poor quality, which urgently needs to be supplemented with similar studies to help understand the current situation.

Furthermore, through the analysis of the results, we found a very interesting phenomenon. The rate of HIV/HBV/HDV triple infection was higher in people with HBV monoinfection than in people with HIV monoinfection or people with HBV/HIV coinfection. However, the credibility and reason for these findings are still unclear, and a large number of clinical studies is needed to better confirm the results.

There were several limitations in this systematic review. Although strict inclusion and exclusion criteria were established and the quality of the included literature was evaluated using the NOS or AHRQ statement entries during the search and screening processes, there was still some subjectivity in the evaluation of the literature due to the lack of accepted quality evaluation criteria, which may lead to some selection bias in the included literature. The results of the sensitivity analysis in this systematic review showed that there was a certain selection bias. In addition, the wide inclusion criteria in this study produced significant heterogeneity that could not be explained. We used a random effects model with subgroup analyses whenever possible to reduce the effect of heterogeneity. Furthermore, the population included in this meta-analysis included people with HBV infection or HIV, lacking a comparable general population; some of these patients were drug users, which would increase the overall prevalence to some extent; and the evidence base had some shortcomings.

In summary, the prevalence of HIV/HBV/HDV triple infection in the global population is underestimated. Therefore, during the management and antiviral treatment of patients with HBV/HIV single infection or coinfection, they should be screened for HIV/HBV/HDV triple infection in a timely manner. In addition, the prevention and treatment of coinfection should be combined with antiviral treatment to provide comprehensive prevention and treatment of triple infection and improve the quality of survival for this population. Additionally, the rates of triple infection in the two special groups of men who have sex with men and people with IDU are also worthy of attention. However, because there are few relevant studies, it is impossible to accurately evaluate the current status of rates of triple infection in the global populations of men who have sex with men and people with IDU [43,44]. More research is urgently needed to provide evidence, identify high-risk populations, and guide the formulation and improvement of prevention and control strategies for HIV/HBV/HDV infection.