Schistosomiasis, hepatitis B and hepatitis C co-infection

A systematic search of published data during the period 1980–2014was performed. Published papers on epidemiology pathogenesis and outcomes of HBV and schistosomiasis were extracted from relevant studies provided they are written in English or at least their abstracts are in English. Databases were searched using different search engines including Medline, PubMed, MiPc library and Google with the keywords “Hepatitis B virus”, “schistosomiasis”, “epidemiology”, “Africa”’ and “South America” and names of particular countries where they were entered interchangeably. We excluded articles using serological methods to diagnose schistosomiasis.

Published data on HBV and schistosomiasis co-infection is scarce where we found about 15 articles fulfilling our criteria; however, in countries where schistosomiasis is endemic such as Egypt, a high prevalence of HBV and S. mansoni co-infection has been described ranging from 19.6 to 33.0% [20,21]. The prevalence of co-infection among the general population in Brazil is 15.8% [22]. A high (58.4%) prevalence of HBV was reported among Chinese patients with chronic schistosomiasis [23].

Similarly, published data about HCV and schistosomiasis co infection is scanty where only 16 articles could fulfill our criteria. Prevalence rates of HCV infection with wide variations as low as 1% and as high as 50% among patients with schistosomiasis, were reported in different countries [24-26]. Likewise high (40.2%) prevalence of HCV and S. mansoni antibodies were detected among 233 wastewater treatment plants workers [27]. Interestingly, a more recent study among 3,596 Egyptian patients found that 27.3% had both HCV-RNA and schistosomiasis, though a weak point is their reliance on serology to diagnose schistosomiasis, a thing that questions the association between HCV and schsitosomiasis [28]. Nonetheless, in Yemen a group of researchers reported a relationship between S. haematobium and hepatitis B, but no correlation between S. mansoni infection and HBV or HCV [29]. The prevalence of S. mansoni infection was 65.9% in a community-based study in Ethiopia including 2,451 subjects. Moreover, the prevalence of schistosomal periportal thickening/fibrosis (PPT/F) was 4.6%. At least one marker of either HBV or HCV was detected in 43.2% of the subjects, of which 5.3% were HBsAg positive, and 1.3% were anti-HCV [30] positive see Table 1. PPT/F increased significantly and proportionally in terms of prevalence with community prevalence and intensity of S. mansoni infection [30]. It is understandable that HSS renders patients at risk of getting HCV owing to the involvement with the risk factors for both HBV and HCV such as history of treatment with parenteral treatment for schistosomiasis unsterile syringes during mass campaigns, blood transfusion, surgical and endoscopic interventions [21,31-35].

Wahib et al., demonstrated the co-infection of HBV and/or HCV in 120 patients with hepatosplenic schistosomiasis was associated with a marked depression in cell mediated immune responses [36]. Furthermore, Edwards et al., described the effects of hepatotropic virus co-infection during the Th2-dominated granulomatous phase of Schistosomal infection. They used lymphocytic choriomeningitis virus (LCMV) as a model for hepatotropic viruses, and demonstrated the induction of a strong LCMV-specific T cell response, with infiltration of large numbers of LCMV-specific interferon (IFN)-γ-producing CD8+ cells into the liver. This can lead to the down regulation of Th2 cytokine production that is dominant during S. mansoni infection and expeditious hepatotoxicity related morbidity. Moreover, livers of co-infected mice were highly susceptible to viral replication, which correlated with a reduction in intrahepatic type I IFN responses following virus infection [36-38].

HCV infection worsens the outcome of concomitant schistosomiasis and HCV infection, causing advanced liver disease, higher HCV RNA titers, an increase in histological activity index, increased incidence of liver cirrhosis and hepatocellular carcinoma, and increased mortality rate [17,39]. S. mansoni co-infection targets a specific subset of memory CD8+ T cells during HCV infection [40]. The immune response in S. mansoni patients with or without HCV infection was evaluated by assaying the serum levels of IFN-γ and IL-5 to estimate cell mediated immunity and IgE levels to estimate humoral immunity. A shift to T helper (Th)-0 and Th-2 immunity as well as an associated reduction of Th-1 responses( more or less a shift from cellular to humoral immunity) were observed, which might have a role in the persistence and severity of both diseases. Such immunity defects can lead to less HCV clearance [41,42]. S. haematobium soluble egg antigen (SEA) affects the intracellular HCV RNA burden in peripheral mononuclear cells (PBMC) as well as cell proliferation in patients with chronic HCV infection, which is linked, in part, to the direct triggering of viral replication by SEA [43]. Lymphotoxin (LT)-α contributes to inflammatory responses and single-nucleotide polymorphisms (SNP) in the human LT-α gene might have significant effects on individual susceptibility to disease. Individuals with HCV infection alone and those co-infected with schistosoma and HCV (but not those infected with Schistosoma alone) were significantly more likely to carry the LN-α gene mutation than the control subjects [44]. The common IL-10 (−1082, −819 and −592) genotypes/haplotypes were not associated with susceptibility to HCV infection either alone or during co-infection with S. mansoni [45].

Chronic infections with hepatotropic viruses, such as HBV, can lead to liver cirrhosis, and an expected synergistic effect might exacerbate hepatic pathology during concomitant infections of HBV and schistosomiasis. Epidemiological studies were performed to investigate schistosomiasis/HBV co-infections, as no suitable animal models exist. A number of studies proposed an increased susceptibility to HBV caused by schistosomal infections (especially the severe hepatosplenic form) [46,47]. However, this could be explained by the frequent need of schistosomiasis patients for blood transfusion, especially on considering the poor infection control measures in countries where this disease is endemic. In contrast, other studies rejected the thesis stating any relationship between schistosomiasis and HBV [48,49]. Woodchucks are susceptible to infection with both schistosoma and woodchuck hepatitis virus (WHV) [50]. Because HBV and WHV descend from the same family (family Hepadnaviridae), a concomitant infection of schistosomes and WHV in woodchucks might be a suitable animal model for concomitant infection in humans. However, there was no impact of schistosome infection on WHV serum markers [51]. HBV replication was inhibited in transgenic mice [52] during schistosomal infection, where the antiviral effects of schistosomes related to IFN-γ and nitric oxide. Thus, most published studies have found no association between schistosomiasis and worsening of HBV infection [53]. In contrast, other studies described a poor prognosis of HBV when associated with hepatosplenic schistosomiasis [17,24,54]. Interestingly HBV vaccines (both 1st and 2nd generation) can mount an immune response in schistosomiasis patients; however, reduced responses to vaccination were seen in hepatosplenic schistosomiasis [37,55,56]. Therefore, further studies are needed to determine conclusions regarding co-infection schistosomiasis and HBV.

S. mansoni infection increases HCV morbidity and chronicity, which might be referred to antecedent liver decompensation [42,57,58]. Increased HCV RNA titers, histological activity, incidence of cirrhosis/hepatocellular carcinoma, and higher mortality rates were noticed in patients with co-infection [17]. However, a sample size of 17 patients in the previous study is not big enough to draw solid conclusions. Other studies reports found no evidence that schistosomiasis affected the outcome of HCV infected patients [53,59].

Praziquantel is a first line therapy for the management and mass chemotherapy of schistosomiasis, and significantly reduced S. mekongi infection (from 50% to 3%) and the associated severe liver disease [60]. Because it is administered orally, praziquantel avoids the use of needles and therefore lowers the risk of HBV and HCV transmission in low-income countries. In a mouse model, praziquantel improved the immunogenicity of HBV vaccine [38]. Certain therapies used for the treatment of HBV infection have a positive effect on schistosomiasis co-infection [61]. In sixty-seven patients with advanced schistosomiasis and HBV co-infection, the use of Entecavir for 52 weeks improved liver fibrosis markers and the Ishak fibrosis score [61]. In a mouse model of infection with schistosomiasis, the use of pegylated IFN (Peg-IFN)-a drug used in treatment of HCV-significantly reduced the worm load in mice [62]. The use of Peg-IFN could be considered for use in humans to assist patients in whom the currently used oral therapy has failed.

Another important issue in this context is the effect of schistosomiasis-HCV co-infection on the response to HCV treatment where some investigators have proposed that co-infection retards response to this treatment [28]. However, Derbala et al. provided a rather more solid evidence in their clinical trial that co-infection does not affect the response to such therapy [63]. Measures to reduce the transmission of HBV and HCV by attention to hygiene and strict hygienic practices, vaccination, early detection in high-risk populations and treatment will be valuable in reducing the morbidity and mortality associated with schistosomiasis co-infection.

As elimination of schistosomiasis is a global target, there is a need for supplementary tools, such as vaccination, to confer long-term prevention. Different approaches for vaccination development have been tested in animal models with variable immunogenicity including Biomphalaria alexandrina snail nucleoproteins, thyroid hormone receptors and more recently, the use of DNA-Sm-p80, and DNA-Sm14 [64-68]. The development of these vaccines relayed mainly on using a subunit approach where the minimal microbial constituents necessary to surmount an appropriate immune response are incorporated into the vaccine, these constituents were tegument proteins most of the times; nevertheless, despite the potential advantages of subunit vaccines, this method resulted in poorly immunogenic vaccines, a thing that entailed the co-administration with potent adjuvants, and in some cases, the addition of T helper epitopes to evoke a long lasting immune response[69].

Current approaches for HCV vaccine comprise a number of approaches of which are the adoption of recombinant E1 and E2 proteins, manufactured peptides, viral particles, viral vehicles, DNA vaccines, dendritic cells, and prime-boost strategies. Nevertheless, there are a number of problems including restricted humoral and cell mediated responses, low transmission of likely protective viral epitopes, and low efficiency of the adjuvants used in different protocols [70]. However, a greater understanding of co-infection and human trials are required to determine the mechanisms of vaccine-induced immunity, to establish a rational ground for novel vaccines and their optimal design. As a number of combined vaccines including HBV vaccine have been proven efficacious [71,72], a combination of HBV and a future schistosomiasis vaccine might also prove beneficial.