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      Treatment of Helminth Co-Infection in Individuals with HIV-1: A Systematic Review of the Literature

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      PLoS Neglected Tropical Diseases
      Public Library of Science

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          Abstract

          Background and Objectives

          The HIV-1 pandemic has disproportionately affected individuals in resource-constrained settings. It is important to determine if other prevalent infections affect the progression of HIV-1 in co-infected individuals in these settings. Some observational studies suggest that helminth infection may adversely affect HIV-1 progression. We sought to evaluate existing evidence on whether treatment of helminth infection impacts HIV-1 progression.

          Review Methods

          This review was conducted using the HIV/AIDS Cochrane Review Group (CRG) search strategy and guidelines. Published and unpublished studies were obtained from The Cochrane Library (Issue 3, 2006), MEDLINE (November 2006), EMBASE (November 2006), CENTRAL (July 2006), and AIDSEARCH (August 2006). Databases listing conference abstracts and scanned reference lists were searched, and authors of included studies were contacted. Data regarding changes in CD4 count, HIV-1 RNA levels, clinical staging and/or mortality were extracted and compared between helminth-treated and helminth-untreated or helminth-uninfected individuals.

          Results

          Of 6,384 abstracts identified, 15 met criteria for potential inclusion, of which 5 were eligible for inclusion. In the single randomized controlled trial (RCT) identified, HIV-1 and schistosomiasis co-infected individuals receiving treatment for schistosomiasis had a significantly lower change in plasma HIV-1 RNA over three months (−0.001 log 10 copies/mL) compared to those receiving no treatment (+0.21 log 10 copies/mL), (p = 0.03). Four observational studies met inclusion criteria, and all of these suggested a possible beneficial effect of helminth eradication on plasma HIV-1 RNA levels when compared to plasma HIV-1 RNA changes prior to helminth treatment or to helminth-uninfected or persistently helminth-infected individuals. The follow-up duration in these studies ranged from three to six months. The reported magnitude of effect on HIV-1 RNA was variable, ranging from 0.07–1.05 log 10 copies/mL. None of the included studies showed a significant benefit of helminth treatment on CD4 decline, clinical staging, or mortality.

          Conclusion

          There are insufficient data available to determine the potential benefit of helminth eradication in HIV-1 and helminth co-infected adults. Data from a single RCT and multiple observational studies suggest possible benefit in reducing plasma viral load. The impact of de-worming on markers of HIV-1 progression should be addressed in larger randomized studies evaluating species-specific effects and with a sufficient duration of follow-up to document potential differences on clinical outcomes and CD4 decline.

          Author Summary

          Many people living in areas of the world most affected by the HIV/AIDS pandemic are also exposed to other common infections. Parasitic infections with helminths (intestinal worms) are common in Africa and affect over half of the population in some areas. There are plausible biological reasons why treating helminth infections in people with HIV may slow down the progression of HIV to AIDS. Thus, treating people with HIV for helminths in areas with a high prevalence of both HIV and helminth infections may be a feasible strategy to help people with HIV delay progression of their disease or initiation of antiretroviral therapy. After a comprehensive review of the available literature, we conclude that there is not enough evidence to determine whether treating helminth infections in people with HIV is beneficial.

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          Most cited references35

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          Immune regulation by helminth parasites: cellular and molecular mechanisms.

          Immunology was founded by studying the body's response to infectious microorganisms, and yet microbial prokaryotes only tell half the story of the immune system. Eukaryotic pathogens--protozoa, helminths, fungi and ectoparasites--have all been powerful selective forces for immune evolution. Often, as with lethal protozoal parasites, the focus has been on acute infections and the inflammatory responses they evoke. Long-lived parasites such as the helminths, however, are more remarkable for their ability to downregulate host immunity, protecting themselves from elimination and minimizing severe pathology in the host.
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            Immune activation is a dominant factor in the pathogenesis of African AIDS.

            The AIDS epidemic in Africa is very different from the epidemic in the West. As suggested here by Zvi Bentwich, Alexander Kalinkovich and Ziva Weisman, this appears to be primarily a consequence of the over-activation of the immune system in the African population, owing to the extremely high prevalence of infections, particularly helminthic, in Africa. Such activation shifts the cytokine balance towards a T helper 0/2 (Th0/2)-type response, which makes the host more susceptible to infection with human immunodeficiency virus (HIV) and less able to cope with it.
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              Identification of tgh-2, a filarial nematode homolog of Caenorhabditis elegans daf-7 and human transforming growth factor beta, expressed in microfilarial and adult stages of Brugia malayi.

              A novel member of the transforming growth factor beta (TGF-beta) family has been identified in the filarial nematode parasite Brugia malayi by searching the recently developed Expressed Sequence Tag (EST) database produced by the Filarial Genome Project. Designated tgh-2, this new gene shows most similarity to a key product regulating dauer larva formation in Caenorhabditis elegans (DAF-7) and to the human down-modulatory cytokine TGF-beta. Homology to DAF-7 extends throughout the length of the 349-amino-acid (aa) protein, which is divided into an N-terminal 237 aa, including a putative signal sequence, a 4-aa basic cleavage site, and a 108-aa C-terminal active domain. Similarity to human TGF-beta is restricted to the C-terminal domain, over which there is a 32% identity between TGH-2 and TGF-beta1, including every cysteine residue. Expression of tgh-2 mRNA has been measured over the filarial life cycle. It is maximal in the microfilarial stage, with lower levels of activity around the time of molting within the mammal, but continues to be expressed by mature adult male and female parasites. Expression in both the microfilaria, which is in a state of arrested development, and the adult, which is terminally differentiated, indicates that tgh-2 may play a role other than purely developmental. This is consistent with our observation that TGH-2 is secreted by adult worms in vitro. Recombinant TGH-2 expressed in baculovirus shows a low level of binding to TGF-beta-receptor bearing mink lung epithelial cells (MELCs), which is partially inhibited (16 to 39%) with human TGF-beta, and activates plasminogen activator inhibitor-1 transcription in MELCs, a marker for TGF-beta-mediated transduction. Further tests will be required to establish whether the major role of B. malayi TGH-2 (Bm-TGH-2) is to modulate the host immune response via the TGF-beta pathway.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                December 2007
                19 December 2007
                : 1
                : 3
                : e102
                Affiliations
                [1]Department of Medicine, University of Washington, Seattle, Washington, United States of America
                London School of Hygiene & Tropical Medicine, United Kingdom
                Author notes

                Conceived and designed the experiments: GJ JW. Analyzed the data: GJ JW. Wrote the paper: GJ JW.

                Article
                07-PNTD-RA-0148R3
                10.1371/journal.pntd.0000102
                2154389
                18160978
                a0a71e03-e052-4671-90e8-b62f5281670d
                Walson, John-Stewart. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 26 June 2007
                : 11 September 2007
                Page count
                Pages: 9
                Categories
                Research Article
                Infectious Diseases/Helminth Infections
                Infectious Diseases/HIV Infection and AIDS
                Infectious Diseases/Neglected Tropical Diseases

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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