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. 2011;6(5):e19841.
doi: 10.1371/journal.pone.0019841. Epub 2011 May 18.

Hepatitis B infection is associated with asymptomatic malaria in the Brazilian Amazon

Bruno B Andrade  1 , Cristiane J N Santos, Luís M Camargo, Sebastião M Souza-Neto, Antonio Reis-Filho, Jorge Clarêncio, Vitor R R Mendonça, Nívea F Luz, Erney P Camargo, Aldina Barral, Antônio A M Silva, Manoel Barral-Netto
Affiliations

Hepatitis B infection is associated with asymptomatic malaria in the Brazilian Amazon

Bruno B Andrade et al. PLoS One. 2011.

Abstract

Background: Areas that are endemic for malaria are also highly endemic for hepatitis B virus (HBV) infection. Nevertheless, it is unknown whether HBV infection modifies the clinical presentation of malaria. This study aimed to address this question.

Methodology and findings: An observational study of 636 individuals was performed in Rondônia, western Amazon, Brazil between 2006 and 2007. Active and passive case detections identified Plasmodium infection by field microscopy and nested Polymerase Chain Reaction (PCR). HBV infections were identified by serology and confirmed by real-time PCR. Epidemiological information and plasma cytokine profiles were studied. The data were analyzed using adjusted multinomial logistic regression. Plasmodium-infected individuals with active HBV infection were more likely to be asymptomatic (OR: 120.13, P<0.0001), present with lower levels of parasitemia and demonstrate a decreased inflammatory cytokine profile. Nevertheless, co-infected individuals presented higher HBV viremia. Plasmodium parasitemia inversely correlated with plasma HBV DNA levels (r = -0.6; P = 0.0003).

Conclusion: HBV infection diminishes the intensity of malaria infection in individuals from this endemic area. This effect seems related to cytokine balance and control of inflammatory responses. These findings add important insights to the understanding of the factors affecting the clinical outcomes of malaria in endemic regions.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Screening and enrollment.
The study participants were stratified according to the clinical presentation of Plasmodium sp. infection (non-infected, asymptomatic and symptomatic malaria). Simultaneously, the presence of HBV infection was verified to identify co-infections.
Figure 2
Figure 2. Adjusted multinomial logistic regression analysis of risk factors for asymptomatic malaria infection or for no malaria infection compared to symptomatic malaria.
Symptomatic malaria infection was considered the primary outcome. Adjustment was performed for all variables presented. CI: Confidence interval. Individuals presenting AgHBS−/anti-HBS+/anti-HBc+ with no HBV DNA amplification by quantitative RT-PCR (qPCR) were considered to have previous HBV infection, those presenting AgHBS+/anti-HBS− and detectable viremia by qPCR were considered currently infected with HBV and those with AgHBS−/anti-HBS+/anti-HBc− were considered vaccinated against the virus. The statistical significance was estimated through multinomial logistic regression.
Figure 3
Figure 3. Individuals co-infected with Plasmodium sp. and HBV present lower parasitemia and higher viremia.
(A) Individuals presenting with symptomatic or asymptomatic malaria were stratified according to the HBV status, and parasitemia levels were determined by light microscopy as described in the methods. The number of participants in each group is described in Table 1. Values were compared by the Kruskal-Wallis test with Dunn's multiple comparisons posttest. (B) HBV viremia was estimated by real-time PCR in both HBV infected (n = 29) or HBV-malaria co-infected (n = 32) individuals using the Mann-Whitney test and the percentage of HBeAg positive cases was also compared to these groups (C) using Fisher's exact test. Lines and boxes represent medians and interquartile ranges, and whiskers represent minimum and maximum values. (D) Spearman correlation between Plasmodium parasitemia and HBV viremia in co-infected individuals (n = 32). A non-linear curve fit was used to illustrate the general trend of the correlation. *P<0.05; ***P<0.0001.
Figure 4
Figure 4. Co-infection with Plasmodium and HBV alters plasma cytokine profile.
Plasma levels of IFN-γ, IL-10 and TNF-alpha were compared between individuals currently infected with HBV (n = 29) and those co-infected with HBV and malaria (n = 32). Lines and boxes represent median and interquartile range, and whiskers represent minimum and maximum values. Data were compared using a Mann-Whitney test. P values are shown in each graph.
Figure 5
Figure 5. HBV infection did not alter either laboratory markers of organic dysfunction or the prevalence of symptoms in malaria cases.
The study participants were stratified according to the clinical presentation of Plasmodium infection and also according to the HBV natural exposure and plasma levels of (A) alanine-aminotransferase (ALT), (B) total bilirubin, (C) C-reactive protein and (D) fibrinogen were compared using a Kruskal-Wallis test with Dunn's multiple comparisons. Lines and boxes represent medians and interquartile ranges, while whiskers represent minimum and maximum values. (E) The prevalence of diverse malaria-related symptoms was measured in individuals presenting with symptomatic malaria and compared between those with previous or current HBV infection and those with no markers of HBV exposure. The values were compared using Chi-square test and no significant differences were found.
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