HIV and helminths: time for a new direction

Abstract

In the mid-1990s, in-vitro data suggested an immunological interaction between HIV and helminth co-infections.1Bentwich Z Weisman Z Moroz C et al.Immune dysregulation in Ethiopian immigrants in Israel: relevance to helminth infections?.Clin Exp Immunol. 1996; 103: 239-243Crossref PubMed Scopus (121) Google Scholar Investigators subsequently tested the hypothesis that helminth infections adversely affect HIV disease progression. Initial small studies2Wolday D Mayaan S Mariam ZG Berhe N et al.Treatment of intestinal worms is associated with decreased HIV plasma viral load.J Acquir Immune Defic Syndr. 2002; 31: 56-62Crossref PubMed Scopus (102) Google Scholar suggested that in-vivo HIV viral load reductions correlated with helminth treatment. Reducing Th2 immunostimulation induced by helminth infection seemed to enhance HIV control, suggesting helminth treatment could be used as an adjunctive immunomodulation therapy. Subsequently, however, at least 12 observational studies and randomised controlled trials have not shown a consistent, clinically significant interaction between HIV and helminth infections.3Walson JL Herrin BR John-Stewart G Deworming helminth co-infected individuals for delaying HIV disease progression.Cochrane Database Syst Rev. 2009; 3 (CD006419.)PubMed Google ScholarJudd Walson and colleagues4Walson J Singa B Sangaré L et al.Empiric deworming to delay HIV disease progression in adults with HIV who are ineligible for initiation of antiretroviral treatment (the HEAT study): a multi-site, randomised trial.Lancet Infect Dis. 2012; 12: 925-932Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar reported results from a large, unblinded, randomised trial of empirical deworming on the natural history of HIV. The investigators reported no treatment effect on CD4 cell count, viral load, time to antiretroviral drug initiation, or mortality. The study was well designed and powered to test its hypothesis. In an accompanying Comment, Zilungile Mkhize-Kwitshana and Musawenkos Mabaso5Mkhize-Kwitshana Z Mabaso M Can deworming delay immunosuppression in HIV?.Lancet Infect Dis. 2012; 12: 899-900Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar question the validity of Walson and colleague's findings. They cite the absence of a baseline assessment of helminths, although 948 patients were randomly assigned and at the final visit helminth prevalence was 2% in the treatment group and 16% in the control group. Additionally, secondary sensitivity analyses showed no difference in any study outcome. The commentators believe that the low prevalence of helminth infection might have biased the results toward the null hypothesis.I believe, in contrast, that Walson and colleagues' Kenyan study is highly compatible with previous studies in populations of both high and low helminth prevalence (irrespective of species) that have also not reported a significant effect on HIV progression. After two decades of mostly negative studies, the time is ripe for innovation, guided by biological plausibility and promising data. The evidence, to date, points to the following three key priorities for future research: the immunological and physical effect of Schistosoma haematobium infections on HIV acquisition; the effect of helminthiasis on vaccine responses in individuals with HIV; and the interaction between intestinal helminths and HIV in children who harbour higher burdens of both pathogens. Despite a dearth of evidence for anthelmintics in the slowing of HIV progression, deworming campaigns should remain a priority within HIV control programmes: the extensive clinical infrastructure available to treat HIV, the overlapping geographic and demographic distributions, the low cost and ease of helminth treatment, and the inherent morbidity of helminth infections themselves all justify this.I declare that I have no conflicts of interest. In the mid-1990s, in-vitro data suggested an immunological interaction between HIV and helminth co-infections.1Bentwich Z Weisman Z Moroz C et al.Immune dysregulation in Ethiopian immigrants in Israel: relevance to helminth infections?.Clin Exp Immunol. 1996; 103: 239-243Crossref PubMed Scopus (121) Google Scholar Investigators subsequently tested the hypothesis that helminth infections adversely affect HIV disease progression. Initial small studies2Wolday D Mayaan S Mariam ZG Berhe N et al.Treatment of intestinal worms is associated with decreased HIV plasma viral load.J Acquir Immune Defic Syndr. 2002; 31: 56-62Crossref PubMed Scopus (102) Google Scholar suggested that in-vivo HIV viral load reductions correlated with helminth treatment. Reducing Th2 immunostimulation induced by helminth infection seemed to enhance HIV control, suggesting helminth treatment could be used as an adjunctive immunomodulation therapy. Subsequently, however, at least 12 observational studies and randomised controlled trials have not shown a consistent, clinically significant interaction between HIV and helminth infections.3Walson JL Herrin BR John-Stewart G Deworming helminth co-infected individuals for delaying HIV disease progression.Cochrane Database Syst Rev. 2009; 3 (CD006419.)PubMed Google Scholar Judd Walson and colleagues4Walson J Singa B Sangaré L et al.Empiric deworming to delay HIV disease progression in adults with HIV who are ineligible for initiation of antiretroviral treatment (the HEAT study): a multi-site, randomised trial.Lancet Infect Dis. 2012; 12: 925-932Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar reported results from a large, unblinded, randomised trial of empirical deworming on the natural history of HIV. The investigators reported no treatment effect on CD4 cell count, viral load, time to antiretroviral drug initiation, or mortality. The study was well designed and powered to test its hypothesis. In an accompanying Comment, Zilungile Mkhize-Kwitshana and Musawenkos Mabaso5Mkhize-Kwitshana Z Mabaso M Can deworming delay immunosuppression in HIV?.Lancet Infect Dis. 2012; 12: 899-900Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar question the validity of Walson and colleague's findings. They cite the absence of a baseline assessment of helminths, although 948 patients were randomly assigned and at the final visit helminth prevalence was 2% in the treatment group and 16% in the control group. Additionally, secondary sensitivity analyses showed no difference in any study outcome. The commentators believe that the low prevalence of helminth infection might have biased the results toward the null hypothesis. I believe, in contrast, that Walson and colleagues' Kenyan study is highly compatible with previous studies in populations of both high and low helminth prevalence (irrespective of species) that have also not reported a significant effect on HIV progression. After two decades of mostly negative studies, the time is ripe for innovation, guided by biological plausibility and promising data. The evidence, to date, points to the following three key priorities for future research: the immunological and physical effect of Schistosoma haematobium infections on HIV acquisition; the effect of helminthiasis on vaccine responses in individuals with HIV; and the interaction between intestinal helminths and HIV in children who harbour higher burdens of both pathogens. Despite a dearth of evidence for anthelmintics in the slowing of HIV progression, deworming campaigns should remain a priority within HIV control programmes: the extensive clinical infrastructure available to treat HIV, the overlapping geographic and demographic distributions, the low cost and ease of helminth treatment, and the inherent morbidity of helminth infections themselves all justify this. I declare that I have no conflicts of interest. Empiric deworming to delay HIV disease progression in adults with HIV who are ineligible for initiation of antiretroviral treatment (the HEAT study): a multi-site, randomised trialOur findings do not suggest an effect of empiric deworming in the delaying of HIV disease progression in adults with HIV in an area where helminth infection is common. Alternative approaches are needed to delay HIV disease progression in areas where co-infections are common. Full-Text PDF