Elsevier

The Lancet

Volume 388, Issue 10054, 15–21 October 2016, Pages 1912-1920
The Lancet

Articles
Effect of Wuchereria bancrofti infection on HIV incidence in southwest Tanzania: a prospective cohort study

https://doi.org/10.1016/S0140-6736(16)31252-1Get rights and content

Summary

Background

The past decades have seen an ongoing controversial debate about whether the immune activation induced by helminths has an effect on the susceptibility of individuals to HIV. In view of this, we assessed the effect of lymphatic filariasis, a chronic helminth disease elicited by Wuchereria bancrofti, on HIV incidence in southwest Tanzania.

Methods

In this population-based cohort study, we enrolled a geographically stratified randomly chosen sample of about 10% of the households in nine distinct sites in southwest Tanzania. All household members present were followed up and tested for HIV and circulating filarial antigen, an indicator of W bancrofti adult worm burden. Our main outcome of interest was HIV incidence in participants with or without lymphatic filariasis.

Findings

Between May 29, 2006, and June 16, 2011, we enrolled 4283 households with roughly 18 000 participants. Of these, 2699 individuals from Kyela district participated in at least one round of the EMINI study. In the 1055 initially HIV-negative adolescents and adults with clearly defined lymphatic filariasis status, 32 new HIV infections were observed in 2626 person-years. HIV incidence in lymphatic filariasis-positive participants (1·91 cases per 100 person-years) was significantly higher than the incidence in lymphatic filariasis-negative participants (0·80 cases per 100 person-years). The age-adjusted and sex-adjusted incidence rate ratio was 2·17 (95% CI 1·08–4·37, p=0·0300). Lymphatic filariasis status remained an independent and significantly relevant risk factor for HIV infection when controlled for other known risk factors such as sexual behaviour and socioeconomic factors.

Interpretation

To our knowledge, this is the first prospective study demonstrating a significantly increased risk of acquiring HIV for lymphatic filariasis-infected individuals. Immunological studies and interventional treatment studies that eliminate the adult worms and not only the microfilariae are needed to follow up on the results presented.

Funding

European Union as part of EuropAid; German Federal Ministry of Education and Research; German Center for Infection Research.

Introduction

The disproportionately high prevalence of HIV in communities of sub-Saharan Africa has led to the hypothesis that concomitant parasitic infections might increase the risk of HIV transmission.1, 2 The foundation of this premise has been based on cross-sectional studies of Ethiopian immigrants in Israel since correlations were observed between the prevalence of helminth and HIV infections.3 An underlying mechanism for this occurrence is that the immune milieu induced by helminth infections could facilitate HIV acquisition.4 In those participants who were predominantly infected with soil-transmitted helminths, immunological changes were characterised by a dominant T-helper-2 cell response and broad T-cell activation.5, 6 Moreover, an increased susceptibility for HIV in peripheral blood mononuclear cells of these immigrants was found through in vitro experimentation.7

Further support that helminths affect HIV susceptibility stems from several cross-sectional studies8 that have reported a positive association of urogenital schistosomiasis with HIV prevalence. By contrast with soil and vector-transmitted helminths, infections with Schistosoma haematobium are located in the urogenital tract and it seems that the disruption of the mucosal barrier is the prevailing factor for increased susceptibility to the virus.9 With regards to filarial nematode infections, no studies have addressed the effect on HIV incidence in endemic communities. Lymphatic filariasis is a chronic helminth disease that infects 120 million people worldwide and is elicited by Wuchereria bancrofti or Brugia species.10 Adult worms reside in the lymphatic system for many years, producing the transmission life-stage microfilariae. Although most individuals with lymphatic filariasis remain asymptomatic, presenting either patent (with microfilariae) or latent (without microfilariae) states,11 some patients do develop severe pathology (hydrocele or lymphoedema).12 Mass drug administration programmes focus on the interruption of transmission with drugs that target microfilariae. An interesting facet of filarial nematodes is the requirement of the endosymbiont Wolbachia spp for their survival and reproduction. Indeed, this has become the Achilles' heel of filariae because treatment with tetracyclines is additionally macrofilaricidal and can revert and improve pathology.13 Before larger treatment programmes started in 2001, lymphatic filariasis was present in most of the 21 regions of Tanzania, with a reported prevalence in coastal regions of up to 44% (799 of 1829 in Tanga, Tanzania).14 In the southern regions of Tanzania, mass drug administration programmes began in 2009. With regards to HIV, several governmental surveys have documented prevalence.15 The third population-based Tanzanian HIV/AIDS and Malaria Indicator Survey 2011/2012 found a countrywide HIV prevalence of 5% in Tanzanian adults between 15 and 49 years of age, and a 9% prevalence for the same age group in the Mbeya region. Possible effects of lymphatic filariasis infection on the prevalence or pathology of HIV have been previously studied.16, 17, 18, 19 A large cross-sectional prevalence study in northern Tanzania reported an increased HIV prevalence in individuals infected with W bancrofti.17 However, a follow-up study in the same group did not support this association.16 Recent studies18, 20 from Malawi and Tanzania reported no evidence that HIV infection affected lymphatic filariasis epidemiology. Because no prospective study focusing on HIV susceptibility in individuals with lymphatic filariasis has been published to date, we did a large cohort study in individuals from the Mbeya region of Tanzania, an area highly endemic for both diseases.15

Research in context

Evidence before the study

We searched PubMed on April 15, 2016, for studies published in English using the search terms “lymphatic filariasis”, “Wuchereria bancrofti”, and “HIV” with no restrictions on publication date. We found few manuscripts describing co-infections of both diseases, which have been cited and discussed in this manuscript. Helminth infections have been suggested as one of the factors driving the HIV/AIDS epidemic in sub-Saharan Africa. However, not many studies have examined the interaction of W bancrofti, a mosquito-transmitted filarial nematode, and HIV, and all of them have focused on already co-infected individuals. A cross-sectional study in north Tanzania suggested a higher HIV prevalence in W bancrofti-positive individuals, but a follow-up study of the same group did not provide evidence for an interaction of lymphatic filariasis with HIV. Recent reports from India, Zimbabwe, and south Tanzania did not show any difference in lymphatic filariasis prevalence or circulating filarial antigen levels in HIV-positive compared with HIV-negative individuals. However, none of the published reports focused on the effect of lymphatic filariasis on HIV transmission.

Added value of the study

The risk for HIV infection is determined by multiple factors, most of which are behavioural. This study describes an increased HIV infection risk caused by a helminth infection (lymphatic filariasis). Our findings open up new opportunities for prevention, especially in the high-HIV-risk group of young adults in developing countries. Furthermore they support the primarily laboratory-based hypothesis that an immune-activated host is more receptive for HIV infection, which if investigated further might improve our understanding of the physiopathology during primary HIV infection.

Implications of all the available evidence

The adult worm of W bancrofti lives for 10–12 years in the lymphatic system and is not killed by single-dose treatment. By contrast, it takes up to 10 years of annual mass treatment to produce a lasting reduction in lymphatic filariasis prevalence in an affected area. Lymphatic filariasis eradication programmes in the past decade have focused on the reduction of transmission but made only limited efforts to cure W bancrofti infection, although recently an active therapy has become available. Lymphatic filariasis, together with other helminth infections, belongs to the 17 neglected diseases as defined by WHO. Our findings add another argument to push neglected diseases, in this case filarial infection, into the focus of global strategies, as they create not only morbidity but in addition generate an increased risk of acquiring HIV.

Section snippets

Study design and participants

The EMINI study was a population-based cohort study done to assess and monitor the effect of future interventions done in the area of infectious disease control (eg, HIV, tuberculosis, malaria, neglected tropical diseases). We enrolled a geographically stratified random sample of about 10% of the households in nine distinct sites. There were no exclusion criteria except for unwillingness to participate or to donate a biological sample. The overarching aim of the cohort was to describe the

Results

The EMINI study was conducted between May 29, 2006, and June 26, 2011. We enrolled 4283 households with roughly 18 000 participants. At the Kyela site, about 88% of participants of each previous year were followed up in the consecutive year. Kyela was visited five times between Feb 16, 2007, and June 10, 2011 (once a year). 2699 individuals from Kyela district participated in at least one round of the EMINI study (figure 1). 51% of participants were female, and the overall median age of the

Discussion

Our study shows a significantly increased risk of acquiring HIV in individuals infected with lymphatic filariasis. Our data were obtained in an area with high prevalence for both HIV and lymphatic filariasis infection at a time when antiretroviral treatment was not widely available, and mass drug administration only began in 2009, affecting the last 2 years of the study.15, 20 The most dominant association between lymphatic filariasis and HIV was in the adolescent group where more than a

References (28)

  • O Shapira-Nahor et al.

    Increased susceptibility to HIV-1 infection of peripheral blood mononuclear cells from chronically immune-activated individuals

    AIDS

    (1998)
  • EF Kjetland et al.

    Association between genital schistosomiasis and HIV in rural Zimbabwean women

    AIDS

    (2006)
  • PS Mbabazi et al.

    Examining the relationship between urogenital schistosomiasis and HIV infection

    PLoS Negl Trop Dis

    (2011)
  • PJ Hotez et al.

    Neglected tropical diseases in sub-saharan Africa: review of their prevalence, distribution, and disease burden

    PLoS Negl Trop Dis

    (2009)
  • Cited by (38)

    • Dynamic immune markers predict HIV acquisition and augment associations with sociobehavioral factors for HIV exposure

      2022, iScience
      Citation Excerpt :

      However, suppression of HSV-2 with acyclovir was not shown to decrease HIV risk.5 Schistosomiasis and filariasis have also been identified as risk factors for both urogenital inflammation and HIV acquisition in co-endemic regions, although more recent studies have failed to show an association between infection with these parasites and the systemic immune activation that predicted HIV risk in the RZHRG study.36,39,40 Neither of these pathogens are present in the geographic region in which our study took place, although persons in this cohort could have had differential risk of exposure to malaria and arbovirus infections by socioeconomic status.

    • Human Filariasis

      2022, Encyclopedia of Infection and Immunity
    • Podoconiosis – From known to unknown: Obstacles to tackle

      2021, Acta Tropica
      Citation Excerpt :

      Indeed, a significant higher prevalence of STH infections have been observed in podoconiosis patients compared to healthy controls (Taye et al., 2013). In addition, several studies already showed that helminth infections modulate host immunity (Adjobimey and Hoerauf, 2010; Maizels et al., 2018; Ritter et al., 2018; Ritter et al., 2019) and can influence disease outcome of concomitant infections and vaccination efficacy (Santiago and Nutman, 2016; Kroidl et al., 2016; Kabagenyi et al., 2020). Thus, helminth-driven modulation of host immunity might facilitate disease progression or impair treatment efficacy (Famakinde and Adenusi, 2018).

    View all citing articles on Scopus
    View full text