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Treatment of helminth co-infection in HIV-1 infected individuals in resource-limited settings.

  1. Judd L Walson*,
  2. Grace John-Stewart

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 15 APR 2009

Assessed as up-to-date: 13 SEP 2007

DOI: 10.1002/14651858.CD006419.pub2

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How to Cite

Walson JL, John-Stewart G. Treatment of helminth co-infection in HIV-1 infected individuals in resource-limited settings.. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD006419. DOI: 10.1002/14651858.CD006419.pub2.

Author Information

  1. University of Washington, Allergy and Infectious Diseases, Seattle, WA, USA

*Judd L Walson, Allergy and Infectious Diseases, University of Washington, Box 359909, University of Washington, 325 Ninth Avenue, Seattle, WA, 98104, USA. walson@u.washington.edu.

Publication History

  1. Publication Status: Unchanged
  2. Published Online: 15 APR 2009

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This is not the most recent version of the article.View current version (08 Jul 2009)

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Notes
  15. Index terms

Many individuals living in areas of the world hardest hit by the HIV-1 epidemic are also infected with other common pathogens. These infections may have detrimental effects on the host's ability to control the HIV-1 virus (Lawn 2001). Some studies have suggested that these infections may result in a more rapid progression of HIV-1 disease (Wolday 2002). Co-infection with other pathogens may lead to a more rapid destruction of the host immune system, and potentially to earlier progression of HIV-1. Chronic helminth infection may suppress immune responses directed against HIV-1 and concurrent immune activation may directly lead to more rapid loss of CD4 cells in HIV-1 infected individuals (Eggena 2005).

Of the over 25 million people infected with HIV-1 in Africa, it is estimated that as many as half of these individuals may be co-infected with helminths (Fincham 2003; UNAIDS 2004). Helminth infection leads to significant stimulation of the host immune response, as these infections are often characterized by the daily production of millions of eggs, excretory products, and secretions. Helminth-infected individuals display increased levels of eosinophilia, increased IgE levels, and a Th2 immune bias (Bentwich 1996; Kassu 2003). Immunoregulation in response to helminth infection may suppress HIV-1-specific CD4+ and CD8+ proliferation and cytokine production, which may compromise control of HIV-1 replication (Brown 2006). Chronic helminth infection has also been shown to be associated with antigen-specific anergy and hyporesponsiveness, which may also down-regulate control of HIV-1 replication (Borkow 2006). Immune activation may also result in increased cellular susceptibility to HIV-1 infection (Shapira-Nahor 1998). Several clinical studies have suggested that helminth co-infection in HIV-1 infected individuals may result increased plasma levels of HIV-1 RNA, and possibly in more rapid disease progression (Kallestrup 2005; Wolday 2002). Based on these findings, the hypothesis that helminth infection may play an important role in the pathogenesis of HIV-1 in Africa was suggested by Bentwich et al (Bentwich 1995).

In a study of HIV-1-infected and uninfected individuals in Ethiopia, helminth co-infection was associated with increased T-cell activation: anti-helminthic treatment appeared to reduce T-cell activation. In addition, treatment of helminth infection resulted in a significant increase in absolute CD4 counts (192 versus 279 cells/mm3, p=0.002) (Kassu 2003). Another study, conducted in Ethiopia, noted an association between stool helminth burden and plasma HIV-1 RNA levels among individuals with helminth co-infection (p<0.001). Successful treatment of helminth co-infection (clearance of helminth eggs in stool) led to a significant decrease in HIV-1 plasma viral load (-0.36 log10) in these patients (Wolday 2002). However, several subsequent observational studies have shown conflicting results regarding the impact of anti-helminth therapy on CD4 count, HIV-1 viral load, and clinical disease progression (Brown 2004; Elliott 2003; Modjarrad 2005).

As HIV-1 treatment programs are expanded in areas in which both HIV-1 and helminth infections are prevalent, it is important to determine whether treating helminth infection can slow HIV-1 disease progression. Mathematical modeling of potential HIV-1 vaccine efficacy suggests that even a modest 0.5 log reduction in set-point HIV-1 RNA levels could slow the onset of AIDS by 3.5 years and could delay the need for antiretroviral medications by almost a full year (Gupta 2007). If anti-helminthic therapy enables HIV-1-infected individuals to delay initiation of antiretroviral therapy or reduces morbidity and mortality, the public health significance of de-worming HIV-1-infected individuals may be substantial.

In this Cochrane review, we evaluated the evidence to date that treating helminth infection in HIV-1 and helminth co-infected individuals may impact HIV-1 progression by reducing the amount of HIV-1 virus (HIV-1 RNA), attenuating CD4 decline, or delaying the onset of symptoms of AIDS.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Notes
  15. Index terms

To determine if treating helminth infection in individuals with HIV-1 is associated with decreased progression of HIV-1 as measured by CD4 count, HIV-1 viral load or clinical disease progression.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Notes
  15. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomized or quasi-randomized controlled trials. We specified that, should data from clinical trials be insufficient, data from observational studies (e.g. cohort, case-control, and cross-sectional studies) would be considered for inclusion in this review, according to the HIV-1/AIDS Cochrane Review Group policy (HIV-1 CRG). Both interventional clinical trials and observational case control and cohort studies of HIV-1 and helminth co-infected individuals were included. Studies performed in general or specific populations and in both hospitals and/or clinics were included. Studies performed in any country and published in any language were included. Studies that relied on historical controls and ecological studies were excluded, as these provide unreliable data for determining causation and/or association.

 

Types of participants

All HIV-1 infected individuals with and without documented helminth co-infection included in studies assessing the association between helminth co-infection and HIV-1 disease progression. Helminths included were schistosomes, Strongyloides, microfilaria, wookworm, whipworm, Ascaris and Trichostrongylus. Included studies documented helminth infection by direct stool microscopy, concentration techniques, other microscopic methods (such as Kato-Katz), culture of stool samples, antigen testing methods (e.g. ELISA kits), modified Knott's concentration methods for microfilaria, or other immunochromatographic testing methods.

 

Types of interventions

Interventions
Anti-helminthic therapy, defined as any pharmaceutical intervention or interventions approved for use in the eradication of helminth infection in humans. This included the benzimidazoles, ivermectin, praziquantel, diethylcarbamazine, bithionol, oxamniquine, pyrantel and nitazoxanide.

Controls
Another anti-helminthic drug, placebo, no treatment, helminth-uninfected individuals. Pre- and post- anti-helminthic therapy CD4 and viral load changes were also included.

 

Types of outcome measures

The outcome measures evaluated:

1) Levels of HIV-1 RNA
2) Absolute CD4 count, absolute lymphocyte count, CD8 count and CD4/CD8 ratio
3) Clinical disease progression, including mortality
4) Adverse events associated with anti-helminthic therapy were recorded if reported in the studies

 

Search methods for identification of studies

See: HIV-1/AIDS Group methods used in reviews.

See: Cochrane Review Group search strategy.

1. Electronic searching
a. Initially, MEDLINE online (1980 to 2006) was searched in July 2006, using the following search strategy:

1 (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR ( placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow-up studies [mh] OR prospective studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animals [mh] NOT human [mh])
2 "HIV-1 Infections"[MeSH] OR "HIV-1"[MeSH] OR HIV-1 [tw] OR HIV-1*[tw] OR HIV-1-2*[tw] OR HIV-11[tw] OR HIV-12[tw] OR HIV-1 infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "Sexually Transmitted Diseases, Viral"[MeSH:NoExp]
3 BENZIMIDAZOLES OR ALBENDAZOLE OR MEBENDAZOLE OR IVERMECTIN OR PRAZIQUANTEL OR DIETHYLCARBAMAZINE OR BITHIONOL OR OXAMNIQUINE OR PYRANTEL OR NITAZOXANIDE
4 HELMINTHS OR ROUNDWORM OR ROUND WORM OR ROUND-WORM OR ROUNDWORMS OR ROUND WORMS OR ROUND-WORMS OR NEMATODES OR NEMATODE OR CESTODE OR CESTODES OR TAPEWORM OR TAPE WORM OR TAPE-WORM OR TAPEWORMS OR TAPE WORMS OR TAPE-WORMS OR TREMATODE OR TREMATODES OR FLUKE OR FLUKES OR WORM OR WORMS OR PARASITE OR PARASITES OR ASCARIS OR TRICHURIS OR ENTEROBIUS OR STRONGYLOIDE OR STRONGLYLOIDES OR ANCYLOSTOMA OR ANCYLOSTOMAS OR NECATOR OR NECATORS OR HYMENOLEPIS OR PARAGONIMUS OR FASCIOLA OR TAENIIA OR HOOKWORM OR HOOK WORM OR HOOK-WORM OR HOOKWORMS OR HOOK WORMS OR HOOK-WORMS OR WHIPWORM OR WHIP WORM OR WHIP-WORM OR WHIPWORMS OR WHIP WORMS OR WHIP-WORMS OR SHISTOSOMIASIS OR MANSONELLA OR FILARIASIS OR MICROFILARIA OR TRICHOSTRONGYLUS
5 #1 AND #2 AND #3 AND #4

This search yielded 937 abstracts. This search identified only one randomized trial. The search strategy was then modified in November 2006 to include observational studies, as follows:

1 "HIV-1 Infections"[MeSH] OR "HIV-1"[MeSH] OR HIV-1 [tw] OR HIV-1*[tw] OR HIV-1-2*[tw] OR HIV-11[tw] OR HIV-12[tw] OR HIV-1 infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "Sexually Transmitted Diseases, Viral"[MeSH:NoExp]
2 HELMINTHS OR ROUNDWORM OR ROUND WORM OR ROUND-WORM OR ROUNDWORMS OR ROUND WORMS OR ROUND-WORMS OR NEMATODES OR NEMATODE OR CESTODE OR CESTODES OR TAPEWORM OR TAPE WORM OR TAPE-WORM OR TAPEWORMS OR TAPE WORMS OR TAPE-WORMS OR TREMATODE OR TREMATODES OR FLUKE OR FLUKES OR WORM OR WORMS OR PARASITE OR PARASITES OR ASCARIS OR TRICHURIS OR ENTEROBIUS OR STRONGYLOIDE OR STRONGLYLOIDES OR ANCYLOSTOMA OR ANCYLOSTOMAS OR NECATOR OR NECATORS OR HYMENOLEPIS OR PARAGONIMUS OR FASCIOLA OR TAENIIA OR HOOKWORM OR HOOK WORM OR HOOK-WORM OR HOOKWORMS OR HOOK WORMS OR HOOK-WORMS OR WHIPWORM OR WHIP WORM OR WHIP-WORM OR WHIPWORMS OR WHIP WORMS OR WHIP-WORMS OR SHISTOSOMIASIS OR MANSONELLA OR FILARIASIS OR MICROFILARIA OR TRICHOSTRONGYLUS
3 BENZIMIDAZOLES OR ALBENDAZOLE OR MEBENDAZOLE OR IVERMECTIN OR PRAZIQUANTEL OR DIETHYLCARBAMAZINE OR BITHIONOL OR OXAMNIQUINE OR PYRANTEL OR NITAZOXANIDE
4 #2 OR #3\

5 #1 AND #4

This search yielded 3329 abstracts.

b. EMBASE online (1980-2006) was searched in August 2006 using the following search strategy:
1 'human immunodeficiency virus infection'/exp) OR ('human immunodeficiency virus'/exp) OR ((('b cell lymphoma'/de OR 'b cell lymphoma'))) OR (HIV-1:ti OR HIV-1:ab) OR ('HIV-1':ti OR 'HIV-1':ab) OR ('HIV-1-2':ti OR 'HIV-1-2':ab) OR ('human immunodeficiency virus':ti OR 'human immunodeficiency virus':ab) OR ('human immunedeficiency virus':ti OR 'human immunedeficiency virus':ab) OR ('human immune-deficiency virus':ti OR 'human immune-deficiency virus':ab) OR ('human immuno-deficiency virus':ti OR 'human immuno-deficiency virus':ab) OR ('acquired immunodeficiency syndrome':ti OR 'acquired immunodeficiency syndrome':ab) OR ('acquired immuno-deficiency syndrome':ti OR 'acquired immuno-deficiency syndrome':ab) OR ('acquired immune-deficiency syndrome':ti OR 'acquired immune-deficiency syndrome':ab) OR ('acquired immunedeficiency syndrome':ti OR 'acquired immunedeficiency syndrome':ab
2 (random*:ti OR random*:ab) OR (factorial*:ti OR factorial*:ab) OR (cross?over*:ti OR cross?over*:ab OR crossover*:ti OR crossover*:ab) OR (placebo*:ti OR placebo*:ab) OR ((doubl*:ti AND blind*:ti) OR (doubl*:ab AND blind*:ab)) OR ((singl*:ti AND blind*:ti) OR (singl*:ab AND blind*:ab)) OR (assign*:ti OR assign*:ab) OR (allocat*:ti OR allocat*:ab) OR (volunteer*:ti OR volunteer*:ab) OR ('crossover procedure'/de) OR ('double-blind procedure'/de) OR ('single-blind procedure'/de) OR ('randomized controlled trial'/de)
3 'helminths'/de OR 'helminths') OR ('roundworm'/de OR 'roundworm') OR ('round worm'/de OR 'round worm') OR ('round-worm'/de OR 'round-worm') OR roundworms OR 'round worms' OR 'round-worms' OR nematodes OR ('nematode'/de OR 'nematode') OR ('cestode'/de OR 'cestode') OR cestodes OR ('tapeworm'/de OR 'tapeworm') OR ('tape worm'/de OR 'tape worm') OR ('tape-worm'/de OR 'tape-worm') OR tapeworms OR 'tape worms' OR 'tape-worms' OR ('trematode'/de OR 'trematode') OR trematodes OR ('fluke'/de OR 'fluke') OR flukes OR ('worm'/de OR 'worm') OR worms OR ('parasite'/de OR 'parasite') OR ('parasites'/de OR 'parasites') OR ('ascaris'/de OR 'ascaris') OR ('trichuris'/de OR 'trichuris') OR ('enterobius'/de OR 'enterobius') OR strongyloide OR stronglyloides OR ('ancylostoma'/de OR 'ancylostoma') OR ancylostomas OR ('necator'/de OR 'necator') OR necators OR ('hymenolepis'/de OR 'hymenolepis') OR ('paragonimus'/de OR 'paragonimus') OR ('fasciola'/de OR 'fasciola') OR taeniia OR ('hookworm'/de OR 'hookworm') OR ('hook worm'/de OR 'hook worm') OR ('hook-worm'/de OR 'hook-worm') OR hookworms OR 'hook worms' OR 'hook-worms' OR ('whipworm'/de OR 'whipworm') OR 'whip worm' OR 'whip-worm' OR whipworms OR 'whip worms' OR 'whip-worms' OR shistosomiasis OR ('mansonella'/de OR 'mansonella') OR ('filariasis'/de OR 'filariasis') OR ('microfilaria'/de OR 'microfilaria') OR ('trichostrongylus'/de OR 'trichostrongylus'
4 'benzimidazoles'/de OR 'benzimidazoles') OR ('albendazole'/de OR 'albendazole') OR ('mebendazole'/de OR 'mebendazole') OR ('ivermectin'/de OR 'ivermectin') OR ('praziquantel'/de OR 'praziquantel') OR ('diethylcarbamazine'/de OR 'diethylcarbamazine') OR ('bithionol'/de OR 'bithionol') OR ('oxamniquine'/de OR 'oxamniquine') OR ('pyrantel'/de OR 'pyrantel') OR ('nitazoxanide'/de OR 'nitazoxanide'
5 #3 OR #4
6 #1 AND #2 AND #5

This search yielded 91 abstracts. Again, in November 2006, this search was modified, as follows:

1 '(human immunodeficiency virus infection'/exp) OR ('human immunodeficiency virus'/exp) OR ((('b cell lymphoma'/de OR 'b cell lymphoma'))) OR (HIV-1:ti OR HIV-1:ab) OR ('HIV-1':ti OR 'HIV-1':ab) OR ('HIV-1-2':ti OR 'HIV-1-2':ab) OR ('human immunodeficiency virus':ti OR 'human immunodeficiency virus':ab) OR ('human immunedeficiency virus':ti OR 'human immunedeficiency virus':ab) OR ('human immune-deficiency virus':ti OR 'human immune-deficiency virus':ab) OR ('human immuno-deficiency virus':ti OR 'human immuno-deficiency virus':ab) OR ('acquired immunodeficiency syndrome':ti OR 'acquired immunodeficiency syndrome':ab) OR ('acquired immuno-deficiency syndrome':ti OR 'acquired immuno-deficiency syndrome':ab) OR ('acquired immune-deficiency syndrome':ti OR 'acquired immune-deficiency syndrome':ab) OR ('acquired immunedeficiency syndrome':ti OR 'acquired immunedeficiency syndrome':ab)
2 ('helminths'/de OR 'helminths') OR ('roundworm'/de OR 'roundworm') OR ('round worm'/de OR 'round worm') OR ('round-worm'/de OR 'round-worm') OR roundworms OR 'round worms' OR 'round-worms' OR nematodes OR ('nematode'/de OR 'nematode') OR ('cestode'/de OR 'cestode') OR cestodes OR ('tapeworm'/de OR 'tapeworm') OR ('tape worm'/de OR 'tape worm') OR ('tape-worm'/de OR 'tape-worm') OR tapeworms OR 'tape worms' OR 'tape-worms' OR ('trematode'/de OR 'trematode') OR trematodes OR ('fluke'/de OR 'fluke') OR flukes OR ('worm'/de OR 'worm') OR worms OR ('parasite'/de OR 'parasite') OR ('parasites'/de OR 'parasites') OR ('ascaris'/de OR 'ascaris') OR ('trichuris'/de OR 'trichuris') OR ('enterobius'/de OR 'enterobius') OR strongyloide OR stronglyloides OR ('ancylostoma'/de OR 'ancylostoma') OR ancylostomas OR ('necator'/de OR 'necator') OR necators OR ('hymenolepis'/de OR 'hymenolepis') OR ('paragonimus'/de OR 'paragonimus') OR ('fasciola'/de OR 'fasciola') OR taeniia OR ('hookworm'/de OR 'hookworm') OR ('hook worm'/de OR 'hook worm') OR ('hook-worm'/de OR 'hook-worm') OR hookworms OR 'hook worms' OR 'hook-worms' OR ('whipworm'/de OR 'whipworm') OR 'whip worm' OR 'whip-worm' OR whipworms OR 'whip worms' OR 'whip-worms' OR shistosomiasis OR ('mansonella'/de OR 'mansonella') OR ('filariasis'/de OR 'filariasis') OR ('microfilaria'/de OR 'microfilaria') OR ('trichostrongylus'/de OR 'trichostrongylus')
3 ('benzimidazoles'/de OR 'benzimidazoles') OR ('albendazole'/de OR 'albendazole') OR ('mebendazole'/de OR 'mebendazole') OR ('ivermectin'/de OR 'ivermectin') OR ('praziquantel'/de OR 'praziquantel') OR ('diethylcarbamazine'/de OR 'diethylcarbamazine') OR ('bithionol'/de OR 'bithionol') OR ('oxamniquine'/de OR 'oxamniquine') OR ('pyrantel'/de OR 'pyrantel') OR ('nitazoxanide'/de OR 'nitazoxanide')
4 #2 OR #3
5 #1 AND #4

This search yielded 2830 abstracts.

c. CENTRAL online (1980-2006) was searched in August 2006 using the following search strategy:
1 HIV-1 OR HIV-1* OR HIV-1-2* OR HIV-11 OR HIV-12 OR (HIV-1 INFECT*) OR (HUMAN IMMUNODEFICIENCY VIRUS) OR (HUMAN IMMUNEDEFICIENCY VIRUS) OR (HUMAN IMMUNE-DEFICIENCY VIRUS) OR (HUMAN IMMUNO-DEFICIENCY VIRUS) OR (HUMAN IMMUN* DEFICIENCY VIRUS) OR (ACQUIRED IMMUNODEFICIENCY SYNDROME) OR (ACQUIRED IMMUNEDEFICIENCY SYNDROME) OR (ACQUIRED IMMUNO-DEFICIENCY SYNDROME) OR (ACQUIRED IMMUNE-DEFICIENCY SYNDROME) OR (ACQUIRED IMMUN* DEFICIENCY SYNDROME) in All Fields in all products
2 MeSH descriptor HIV-1 Infections explode all trees in MeSH products
3 MeSH descriptor HIV-1 explode all trees in MeSH products
4 (ANIMAL OR ANIMALS) AND (NOT HUMANS) in All Fields in all products
5 HELMINTHS OR ROUNDWORM OR ROUND WORM OR ROUND-WORM OR ROUNDWORMS OR ROUND WORMS OR ROUND-WORMS OR NEMATODES OR NEMATODE OR CESTODE OR CESTODES OR TAPEWORM OR TAPE WORM OR TAPE-WORM OR TAPEWORMS OR TAPE WORMS OR TAPE-WORMS OR TREMATODE OR TREMATODES OR FLUKE OR FLUKES OR WORM OR WORMS OR PARASITE OR PARASITES OR ASCARIS OR TRICHURIS OR ENTEROBIUS OR STRONGYLOIDE OR STRONGLYLOIDES OR ANCYLOSTOMA OR ANCYLOSTOMAS OR NECATOR OR NECATORS OR HYMENOLEPIS OR PARAGONIMUS OR FASCIOLA OR TAENIIA OR HOOKWORM OR HOOK WORM OR HOOK-WORM OR HOOKWORMS OR HOOK WORMS OR HOOK-WORMS OR WHIPWORM OR WHIP WORM OR WHIP-WORM OR WHIPWORMS OR WHIP WORMS OR WHIP-WORMS OR SHISTOSOMIASIS OR MANSONELLA OR FILARIASIS OR MICROFILARIA OR TRICHOSTRONGYLUS
6 BENZIMIDAZOLES OR ALBENDAZOLE OR MEBENDAZOLE OR IVERMECTIN OR PRAZIQUANTEL OR DIETHYLCARBAMAZINE OR BITHIONOL OR OXAMNIQUINE OR PYRANTEL OR NITAZOXANIDE
7 #5 OR #6
8 #1 OR #2 OR #3
9 #7 AND #8
10 #9 AND NOT #4 from 1980-2006

This search yielded 69 abstracts.

d. AIDSearch online (1980-2006) was searched in August 2006 using the following search strategy:
1 PT=randomized CONTROLLED TRIAL
2 PT=CONTROLLED CLINICAL TRIAL
3 randomized CONTROLLED TRIALS
4 RANDOM ALLOCATION
5 DOUBLE BLIND METHOD
6 SINGLE BLIND METHOD
7 PT=CLINICAL TRIAL
8 CLINICAL TRIALS OR CLINICAL TRIALS, PHASE 1 OR CLINICAL TRIALS, PHASE II OR CLINICAL TRIALS, PHASE III OR CLINICAL TRIALS, PHASE IV OR CONTROLLED CLINICAL TRIALS OR MULTICENTER STUDIES
9 (SINGL* OR DOUBL* OR TREBL* OR TRIPL*) NEAR6 (BLIND* OR MASK*)
10 CLIN* NEAR6 TRIAL*
11 PLACEBO*
12 PLACEBOS
13 RANDOM*
14 RESEARCH DESIGN
15 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14
16 ANIMALS NOT (HUMAN AND ANIMALS)
17 #15 NOT #16
18 HELMINTHS OR ROUNDWORM OR ROUND WORM OR ROUND-WORM OR ROUNDWORMS OR ROUND WORMS OR ROUND-WORMS OR NEMATODES OR NEMATODE OR CESTODE OR CESTODES OR TAPEWORM OR TAPE WORM OR TAPE-WORM OR TAPEWORMS OR TAPE WORMS OR TAPE-WORMS OR TREMATODE OR TREMATODES OR FLUKE OR FLUKES OR WORM OR WORMS OR PARASITE OR PARASITES OR ASCARIS OR TRICHURIS OR ENTEROBIUS OR STRONGYLOIDE OR STRONGLYLOIDES OR ANCYLOSTOMA OR ANCYLOSTOMAS OR NECATOR OR NECATORS OR HYMENOLEPIS OR PARAGONIMUS OR FASCIOLA OR TAENIIA OR HOOKWORM OR HOOK WORM OR HOOK-WORM OR HOOKWORMS OR HOOK WORMS OR HOOK-WORMS OR WHIPWORM OR WHIP WORM OR WHIP-WORM OR WHIPWORMS OR WHIP WORMS OR WHIP-WORMS OR SHISTOSOMIASIS OR MANSONELLA OR FILARIASIS OR MICROFILARIA OR TRICHOSTRONGYLUS
19 BENZIMIDAZOLES OR ALBENDAZOLE OR MEBENDAZOLE OR IVERMECTIN OR PRAZIQUANTEL OR DIETHYLCARBAMAZINE OR BITHIONOL OR OXAMNIQUINE OR PYRANTEL OR NITAZOXANIDE
20 #18 OR #19
21 #17 AND #20 AND PY=1980-2006

This search yielded 156 abstracts.

2. Reference lists
Reference lists of all the studies that were included in the pool of retrieved studies, including those of other reviews, were examined in order to identify any further studies.

3. Personal contract
We attempted to contact authors for studies initially selected for inclusion in the pool of retrieved studies in order to identify any further studies. Data on CD4 count and HIV-1 RNA levels were requested from authors when not presented in the published manuscripts.

 

Data collection and analysis

The development of search strategy was performed with the assistance of the Cochrane HIV/AIDS Group. The titles, abstracts, and descriptor terms of all downloaded material from the electronic searches were read by JW and GJS and irrelevant reports were discarded. All citations identified were then independently evaluated by JW and GJS to establish relevance of the article according to the pre-specified criteria. When there was uncertainty as to the relevance of the study, the full article was obtained.

1. Selection of studies
JW and GJS independently applied the inclusion criteria. There were no differences requiring a third reviewer to resolve. Studies were reviewed for relevance based on study design, types of participants, exposures, and outcome measures. We sought further information from the authors where papers contained insufficient information to make a decision about eligibility.

2. Data extraction
Data were independently extracted by JW and GJS. Standardized data extraction forms were used. Separate forms were used: one for randomized trials, one for cohort/cross-sectional studies and one for case-control studies.

The following characteristics were extracted from each included study:
·Administrative details: Identification; author(s); published or unpublished; year of publication; year in which study was conducted

·Details of study: Study design; type; duration; completeness of follow-up for cohort studies; country and location of the study; setting (e.g. urban or rural, hospital or clinic); method(s) of recruitment; number of participants

·Characteristics of participants: Age; gender; socioeconomic status; HIV-1 stage if available

·Details of intervention: Medication; dose; duration; number of treatments

·Details of outcomes: Change in HIV-1 RNA; change in CD4 count; change in rate of clinical HIV-1 disease progression (changes in WHO or CDC Staging); mortality

3. Quality assessment
Quality assessment was performed using standardized quality assessment forms.

·Randomized controlled trial: The methodologic quality of the included clinical trial was evaluated independently by authors (JW and GJS), according to a validity checklist for clinical trials (http://www.igh.org/Cochrane). Studies were evaluated for adequacy of allocation concealment. Selection bias was assessed by evaluating the method of generation of allocation sequence and adequacy of allocation concealment. Performance and detection biases were assessed by checking whether participants, investigators, or assessors were blinded. Attrition bias was assessed by the adequacy of follow-up and intention-to-treat analysis. Trials with loss to follow-up ≥20% were rated as adequate and inadequate if unclear or above 20%.

·Observational studies: The authors independently evaluated the methodological quality of the included observational studies using the Newcastle-Ottawa Quality Assessment Scales for observational studies (Wells et al), as recommended by the Cochrane HIV-1/AIDS Group. Assessment of methodological quality for observational studies is detailed below.

Assessment of methodologic quality for observational trials was performed as follows:
(a) External validity
- Was the sample a census, consecutive sample, or random sample?
- Were at least 80% of those eligible to participate in all groups recruited?

(b) Performance bias
- Were assessors of helminth infection status blinded to HIV-1 status?
- Was the same method of ascertainment used in cases and controls?

(c) Detection bias
- Was helminth infection status ascertained by microscopy, culture, and/or immunologic testing?
- Was HIV-1 status ascertained using an ELISA test, Western blot, or particle agglutination test?
- Was HIV-1 status confirmed using a different or second test from this list?
- Were assessors of outcome measures (HIV-1 RNA, CD4 count, clinical stage) blinded to helminth infection status (or were HIV-1 and helminth testing done in independent laboratories)?

(d) Attrition bias
- Were helminth-infected and uninfected groups followed for the same time?
- Were at least 80% of participants in all groups included in the final analysis or was the description of those not included not suggestive of bias?

(e) Selection bias
- Were cases selected from the general population?
- Were controls selected from the same population as the cases?

(f) Control of confounding
- The following factors are pre-specified by the review team as potential confounders. The authors (JW and GJS) will assess whether they are demonstrated to be similar in both groups, matched in the design or adjusted for in the analysis.
(1) age at baseline
(2) study location (urban/rural, vicinity to fresh water sources with known high burden of parasites)
(3) education, occupation, socioeconomic status
(4) marital status
(5) stage of HIV-1 disease
(6) other concurrent infections

4. Data synthesis
Incomplete data: Where data were incomplete, attempts were made to contact the authors for clarification of relevant information.

Randomized clinical trial data were not combined with data from observational studies. Observational studies were grouped and assessed by type (e.g. cohort study, case control study).

Outcome measures: A narrative synthesis was performed. Meta-analysis was not conduced, as only a single randomized trial was identified. All outcomes included in this review were continuous and were assessed with a standardized mean difference (SMD) and 95% confidence interval. We did not statistically pool the outcomes and examine the differences between fixed- and random-effects models, given the degree of heterogeneity between the trials.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Notes
  15. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

We identified five studies that met criteria for inclusion in this review. Only one randomized controlled trial was identified. The four non-RCTs included in this review were all cohort trials.

Studies included in this review: Kallestrup 2005; Brown 2004; Elliott 2003; Modjarrad 2005; Wolday 2002.

Details of each study are given in the table, "Characteristics of included studies" and are noted below:

Kallestrup 2005: A randomized clinical trial of treatment of schistosomiasis to evaluate the effect on HIV-1 was conducted in rural Zimbabwe. The primary objective of the trial was to determine whether treatment of schistosomiasis has an effect on the course of HIV-1 infection, as measured by changes in HIV-1 RNA and CD4 count. Individuals with documented schistosomiasis and with or without HIV-1 were randomized to receive praziquantel therapy at inclusion or after a three-month delay. In this trial, 287 individuals were enrolled, of whom 130 HIV-1 and schistosomiasis co-infected individuals were included. Of these 130 individuals, 64 received early treatment and 66 received delayed therapy. Participants were assessed by clinical exam as well as laboratory determination of CD4 count, plasma HIV-1 RNA, and CDC clinical stage at enrollment and three months after inclusion. Actual changes in CD4 counts and HIV-1 RNA viral loads for the HIV-infected group were not included in the published manuscript, but were provided by the author upon request for inclusion in this review.

Brown 2004: A prospective cohort study examining the effect of treatment of helminths on the course of HIV-1 infection in Uganda. The primary objective of the study was to assess differences in changes in CD4 count and HIV-1 RNA in HIV-1-infected individuals with and without helminth co-infection. This cohort has been followed since 1995, and CD4 count data were available for the six months prior to enrollment. Five hundred forty-seven HIV-1-infected individuals were analyzed, of whom 294 (54%) were helminth co-infected. CD4 count data from the six months prior to enrollment were available for 409 participants, of whom 214 were helminth co-infected. Follow-up data were available for 177 HIV-1 and helminth co-infected participants. All participants were treated empirically with albendazole at enrollment after collection of blood, urine, and stool specimens. Those found to have infection with schistosomiasis were treated with praziquantel after one month. Participants were followed up after six months, at which time blood, urine, and stool were collected again to determine helminth infection status, CD4 count, and HIV-1 RNA levels.

Elliott 2003: A prospective cohort study examining the effect of treatment of helminths on the course of HIV-1 infection in Uganda. The primary objective of the study was to assess differences in change in CD4 count and HIV-1 RNA between HIV-1 and helminth co-infected individuals after treatment of helminth infection and HIV-1 infected individuals without helminth co-infection over four months of follow-up. This is an established cohort of HIV-1 infected individuals, and CD4 counts from participants were available for the six months prior to enrollment. One hundred twenty HIV-1-infected participants were screened for helminths by stool examination and serum CAA for schistosomiasis at enrollment. One hundred eight individuals were included in the analysis, of whom 39 were HIV-1 and helminth co-infected. Data on CD4 counts from six months prior to enrollment were available for 30 of the 39 co-infected individuals. Nematode-infected individuals were treated with mebendazole 100mg twice a day for three days and schistosomiasis was treated with two doses of 20 mg/kg of praziquantel. At the five-week and four-month follow-up visits, participants were again tested for CD4 count and HIV-1 RNA.

Modjarrad 2005: Prospective cohort trial examining the impact of anti-helminthic treatment on HIV-1 RNA concentrations in Zambia. The primary objective of the study was to assess differences in HIV-1 RNA levels between HIV-1 and helminth co-infected individuals who were treated with anti-helminthics and HIV-1-infected, helminth-uninfected individuals who did not receive anti-helminthics. The investigators screened 428 adults for HIV-1 sero-status and assessed helminth infection using stool microscopy. Fifty-four 5 HIV-1 and helminth co-infected individuals were recruited into the study and matched by sex and age (±4yrs) with HIV-1-infected, helminth-uninfected participants. Co-infected individuals were treated at week one and week four following enrollment with albendazole (400mg on the first day and 200mg for two subsequent days) and praziquantel (40mg/kg divided into two doses given four to six hours apart). Participants were followed at four weeks, 10 weeks and 16 weeks following the initiation of treatment. HIV-1 RNA and CD4/CD8 counts were measured at baseline, week one, week 10 and week 16.

Wolday 2002: Prospective cohort trial examining the effect of anti-helminthic treatment on HIV-1 RNA concentrations in Ethiopia. Fifty-six consecutive HIV-1-infected individuals were enrolled and screened for helminths. Each participant submitted two stool samples taken at least four hours apart at each time-point (entry, three months, six months) and each sample was examined using Kato-Katz method and by formalin-ether concentration. Thirty-one participants were helminth co-infected. Data were available for HIV-1 RNA on only 28 of the 56 enrolled participants. All individuals were treated with albendazole 200mg a day for three days at entry, three months, and six months of follow up. Participants with documented schistosomiasis infection were treated with 40mg/kg of praziquantel at these same time-points. Plasma HIV-1 RNA measurements were reported at baseline and at the six-month follow-up visit.

 

Risk of bias in included studies

Only one randomized trial of treatment of helminth co-infection in HIV-1 infected individuals was identified (Kallestrup 2005). Treatment allocation was not concealed from participants or investigators. Outcome comparisons were only made for patients for whom follow-up data were available.

Four observational studies were included. These studies all were determined to have included representative populations of HIV-1 and helminth co-infected individuals. All of the included observational studies made comparisons to a helminth-uninfected comparator group. The assessment of outcome was done by comparing changes in CD4 count and HIV-1 RNA levels over the follow-up period between the helminth-infected group and the helminth-uninfected group. Two of these studies compared changes in CD4 counts in individuals prior to helminth treatment to changes in the same individuals following treatment (Brown 2004; Elliott 2003). The assessment of outcome was done by comparing changes in CD4 count in the six months preceding treatment for helminth co-infection to changes in the same individuals over the course of the follow-up period (Four to six months later). Two of the included observational studies compared individuals who cleared their helminth infection at follow-up with individuals who remained helminth-infected (or were re-infected) at follow-up (Brown 2004; Wolday 2002). Follow-up was judged to be adequate in all included studies. Assessment of the quality of the included studies is provided in the table "Assessment of Non-Randomized Studies" below.

Overall, the quality of the observational studies was variable. A graphic representation of the study quality of each included observational study is presented in  Table 1.

Performance bias (misclassification of exposure) may have occurred in the comparison of individual patient data from a time-point prior to enrollment to data obtained at follow-up (as was done using data from both Brown 2004 and Elliott 2003). The comparison of outcome data from individuals from a period of time prior to the enrollment visit (when confirmation of helminth infection was conducted) with data collected after treatment for helminth infection may have resulted in the misclassification of exposure.

Detection bias may have been present in the included studies, as a detailed explanation of blinding methods for assessing and confirming HIV-1 and helminth infection status was not presented in any of the included studies.

Attrition bias may have been an important problem in the studies by Wolday 2002 and Brown 2004. Data on HIV-1 RNA levels in the Wolday 2002 study were available for only 50% of the enrolled participants. In the study Brown 2004, loss to follow-up for the entire cohort was 22%. The remaining studies all had loss to follow-up rates of less than 20%.

Selection bias was a problem for all studies and the results were potentially confounded by other risk factors for the progression of HIV-1. Patients were grouped according to helminth status at baseline, which may have resulted in differences between the groups confounding the outcomes reported.

 

Effects of interventions

After an expanded search strategy was employed, we identified 6,384 citations. From this list, we identified 15 potentially relevant studies, of which five were determined to be eligible for this review, including one randomized controlled trial (Kallestrup 2005) and four observational studies (Brown 2004; Elliott 2003; Modjarrad 2005; Wolday 2002) (Figure 1). The characteristics of the included studies are presented in Table 1. All of the included studies were conducted in Africa and included HIV-1-infected individuals who were treated for a variety of different helminth infections. Four of the five studies noted that none of the participants were on antiretroviral medication (Elliott 2003; Kallestrup 2005; Modjarrad 2005; Wolday 2002), while in one study (Brown 2004) data on antiretroviral therapy was not provided. In the observational studies, changes in HIV-1 RNA or CD4 were compared between helminth-treated individuals and helminth-uninfected controls, or controls in the period prior to helminth treatment. Three studies also compared changes in HIV-1 RNA or CD4 between treated individuals who cleared their helminth infection at follow-up and individuals who remained infected at follow-up. Unpublished data were requested from the authors of the included observational studies and included in this analysis from three of included observational studies (Brown 2004; Elliott 2003; Kallestrup 2005).

 FigureFigure 1. Flow chart of study selection process

The ten excluded studies, along with the rationale for exclusion, are presented in Table 2. Reasons for exclusion included inadequate reporting or collection of outcome data (Brown 2005; Gallagher 2005; Ganley-Leal 2006; Hosseinipour 2007; Lawn 2000; Kassu 2003; Kelly 1996; Mwanakasale 2003), lack of a control comparison group (Brown 2005; Hosseinipour 2007; Lawn 2000), failure to confirm helminth infection status (Kelly 1996), and reporting of data already presented in another included study (Kallestrup 2006).

The studies were stratified according to study type, i.e., RCT vs. observational. We had pre-specified in our protocol that meta-analysis would be performed if data permitted. Given that only one RCT was identified, and given the highly heterogeneous comparator groups and results, as well as the high likelihood of bias in the observational studies, it was felt that any overall summary statistic would be misleading and a meta-analysis was not performed. Instead, we evaluated the direction and consistency of effect, assessing the likelihood of bias for each included study and investigating factors that may explain the differences observed between the studies. Studies were evaluated using the standardized mean difference (SMD=difference in mean outcome between groups/standard deviation of outcome among participants) (JPT 2005).

The results of the single randomized control trial demonstrated a statistically significant benefit on plasma HIV-1 RNA levels with treatment of schistosomiasis co-infection in HIV-1-infected adults, compared to no treatment over three months of follow-up (Analysis 2) (Kallestrup 2005). Individuals in the treatment group had minimal change in plasma viral load over three months of follow-up (-0.001 log10 copies/mL) compared to an increase in those who did not receive treatment during this period (0.21 log10 copies/mL), (p=0.03). This trial noted a statistically significant benefit on CD4 count with treatment when both HIV-1-infected and HIV-1-uninfected individuals were included, with a non-significant trend for a difference between the two study arms when limited to HIV-1-infected individuals (treatment resulted in a 1.7 cells/µL mean decline compared to a 35.2 cells/µL mean decline in the untreated group (p=0.17) (Unpublished data provided by author). (Analysis 3). This study also evaluated differences in CDC clinical staging between the treated and untreated group. At the three-month visit, there were no differences with regard to the number of individuals in CDC stage A, B, or C (43:20:1 for the treatment arm compared to 44:20:2 in the untreated arm), although the study was underpowered for this assessment.

We stratified the four additional observational studies by outcome variable (HIV-1 RNA or CD4 count) and by comparator group (helminth-uninfected controls, same individuals during interval prior to helminth treatment, or individuals who failed to clear helminths at follow-up).

Study results comparing changes in HIV-1 RNA levels
Helminth-treated versus helminth-uninfected controls
Three observational studies presented data comparing treated HIV-1 helminth co-infected individuals to HIV-1-infected helminth-uninfected controls (Brown 2004; Modjarrad 2005; Wolday 2002) (Analysis 2). The results of all of these studies were in the direction of a benefit in reducing plasma HIV-1 RNA viral load with treatment of helminth co-infection. In the study by Brown et al, participants were screened for helminths and treated with albendazole, regardless of helminth infection status. In the other two studies, helminth-uninfected participants did not receive anti-helminthics. Treatment of helminth-infected participants in the Modjarrad study included both albendazole and praziquantel. The helminth-treated cohort size in these studies ranged from 13 to 163 participants and the helminth-uninfected cohort size ranged from nine to 140 participants. Follow-up was between three and six months. Helminth-treated participants had HIV-1 RNA changes ranging from -0.36 log10 to +0.06 log10 copies/ml following treatment; the standard mean difference in HIV-1 RNA between helminth-treated and the helminth-uninfected individuals followed over the same period ranged from -0.19 to -0.73, all in the direction of decreased HIV-1 RNA or lower plasma HIV-1 RNA increase in helminth-treated individuals compared to helminth-uninfected comparators.

Participants clearing infection at follow-up compared to participants with continued infection at follow-up
Three observational studies compared individuals who cleared their initial helminth infection following treatment to those who were helminth-infected at follow-up (Analysis 2) (Brown 2004; Elliott 2003; Wolday 2002). Two studies showed a trend towards a beneficial effect on plasma viral load with the successful treatment of helminth infection, while one study did not. These cohorts included between 13 and 93 individuals who cleared their helminth infection and between six and 70 comparators who failed to clear helminth infection. Change in plasma HIV-1 RNA ranged from -0.36 to +0.11 log10 copies/ml during three to month months of follow-up in those who cleared their helminth infection, versus changes of -0.03 to +0.69 log10 copies/ml in those who did not (standard mean difference of -0.14 to -1.41).

Study results comparing changes in CD4 counts
Helminth-uninfected controls
Changes in CD4 counts were compared between individuals treated for helminth infection and individuals who were not infected with helminths at baseline in three studies (Analysis 3) (Brown 2004; Elliott 2003; Modjarrad 2005). While there appeared to be a beneficial effect of treatment on CD4 count in all of these studies, none were statistically significant. Over three to six months of follow-up, helminth-treated individuals experienced mean decreases in CD4 counts of 29-48 cells/µL (cohorts of between 30 and 177 individuals) while decreases among individuals without helminth infection ranged from 50-56 cells/µL over the same period (cohorts of between 43 and 153 individuals). The standardized mean difference ranged from -0.01 to -0.23 for these comparisons.

Changes in CD4 counts within individuals prior to and after helminth eradication therapy
Two observational studies compared changes in CD4 counts in a six-month period prior to treatment of helminths to changes observed during follow-up post-treatment in the same individuals (Brown 2004; Elliott 2003). Neither of these studies showed significant differences in CD4 count changes before and after treatment of helminth co-infection. In the six-month period preceding helminth treatment, one study noted a CD4 decline of 36 cells/µL in 177 individuals and a decline of 42 cells/µL in the six months following treatment, while the other study documented a rise in mean CD4 count of three cells/µL among 30 individuals prior to treatment, versus a decline of 29 cells/µL following treatment (unpublished data provided by authors).

Participants clearing infection at follow-up compared to participants with continued infection at follow-up
Changes in CD4 counts between helminth co-infected individuals who cleared their infection following treatment and those who were infected with helminths at the follow-up visit were compared in two studies (Brown 2004; Elliott 2003). In contrast to the expected direction of effect, one study noted that among 104 individuals who cleared their helminth infection, there was a mean decline of 54 cells/µL compared to a decline of 24 cells/µL among 73 individuals with persistent helminth infection (p=0.14). In another study, 21 individuals who cleared their helminth infection had a median increase in CD4 count of 1 cells/µL compared to an increase of 2 cells/µL in 13 individuals with persistent infection (unpublished data provided by authors).

Mortality
Mortality data were presented in three of the included studies. In one study, there were 13 deaths over six months of follow-up among 144 helminth-treated individuals (mortality rate of 90.4 cases/1000 person-years, 95% CI 52.5-155.6) compared to 13 deaths among 122 helminth-uninfected individuals (mortality rate 106.4 cases/1000 person years, 95% CI 61.8-183.3), (difference in mortality, p=0.68) (Brown 2004). In a smaller study, there were two deaths among the 31 treated helminth-infected individuals and two deaths among the 25 helminth-uninfected individuals (Wolday 2002). Finally, in a third study there was one death in each of the groups (helminth-treated and helminth-uninfected) (Modjarrad 2005).

Helminth species-specific effects
The RCT was the only study designed to evaluate the effect of treating a specific helminth (schistosomiasis). There were differences in species-specific prevalence rates reported in each of the included studies (Table 1). The studies by Elliott et al, Brown et al, and Modjarrad et al reported differences between helminth species, although all were underpowered to detect potentially meaningful effects by individual species (Brown 2004; Elliott 2003; Modjarrad 2005). Elliott et al also reported a significant decline in log10 HIV-1 RNA levels among individuals with schistosomiasis (n=24) between five weeks following therapy and the four-month follow-up visit (p=0.01). In contrast to this, Brown et al reported significantly greater decreases in CD4 counts in individuals who successfully cleared their schistosomiasis infection at six months (n=105, mean decrease of 59.8 cells/µL) compared to those who remained persistently infected with schistosomes (n=54, mean decrease of 15.5 cells/µL) (p=0.05). Brown et al also found that among Mansonella perstans-infected subjects, persistent infection at follow-up (n=22) was associated with a decrease from 4.86 to 4.67 log10 HIV-1 RNA (p=0.009).

Adverse events
None of the included trials reported differences in adverse events between the groups compared in this analysis.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Notes
  15. Index terms

It has been suggested that de-worming is unlikely to have an effect on HIV-1 progression in co-infected individuals (Hosseinipour 2007). However, to date there has been only one randomized controlled trial evaluating the potential benefit of treating helminth co-infection in HIV-1 infected individuals that was limited to evaluation of schistosomiasis co-infection. In light of the lack of sufficient evidence from RCT data, we assessed available evidence of the benefits of treating helminths in co-infected individuals available from observational studies. The results of this systematic review demonstrate that there are insufficient data from clinical trials or observational studies to make conclusions regarding the potential impact of de-worming on HIV-1 progression in co-infected individuals.

The only RCT conducted to date demonstrated a statistically and clinically significant difference in change in HIV-1 RNA levels (0.21 log10 HIV-1 RNA) in treated versus untreated individuals with schistosomiasis (Kallestrup 2005). This study failed to show significant differences in changes in CD4 counts or clinical staging between the groups. The study was limited by a lack of allocation concealment, a short follow-up interval (three months), and significant differences at baseline in gender distribution, CD4 counts, and plasma HIV-1 viral loads between randomization groups. In the four observational studies eligible for inclusion in this review, there was also a trend toward a beneficial effect of helminth treatment on HIV-1 RNA levels in co-infected individuals. Again, de-worming did not appear to exert a benefit on CD4 count decline or mortality in these studies, and some studies found greater CD4 decline following successful helminth clearance when compared to persistently infected individuals. Together, the cumulative available evidence suggests a possible benefit of de-worming on plasma HIV-1 RNA levels, but not CD4 counts or clinical status over a short period of follow-up.

In the observational studies reviewed, groups of helminth-treated individuals were compared to three different types of "control" groups, all of which were likely to differ at baseline from the group with helminth infection in which the intervention was administered. Helminth-infected individuals may have pre-existing differences in behavioral, social, nutritional, and biological factors that may have led to helminth infection and may also result in faster HIV-1 progression. A comparator group of helminth co-infected individuals who did not clear their helminth infection is similarly subject to bias, as helminth clearance may be directly related to the capacity of the host immune system to handle such infections, which may also correlate with control of HIV-1. Comparing individual data from a period of time prior to de-worming to data following therapy is also subject to limitations. Individuals may acquire helminth infection during the period between the initial measurement of CD4 count or HIV-1 RNA and the de-worming visit, and this could result in misclassification of the exposure. In addition, rates of change in CD4 count and viral load in HIV-1-infected individuals differ over time, making it difficult to compare changes in these parameters at two different periods within an individual. These limitations compromise the strength of the evidence regarding treatment effect and highlight the need for randomized placebo-controlled trials to determine effects of anti-helminthics on HIV-1 progression.

There are important possible interactions between helminths and HIV-1 that may be dependent on the intensity of helminth infection or differences in the infecting helminth species. Helminth burden has been correlated with HIV-1 RNA levels in HIV-1 co-infected individuals and may be an important factor in determining the extent to which helminths affect HIV-1 progression (Wolday 2002). In addition, helminth species differ in their level of tissue invasiveness, level of resulting host immune activation, and other factors, which may explain observed differences in the interactions between HIV-1 and various helminths seen in observational studies (Brown 2006). All of the included studies were limited by short follow-up duration. The finding of changes in HIV-1 RNA levels, despite the short duration of follow-up, in these studies is perhaps more biologically plausible than a finding of changes in clinical staging or CD4 counts. Helminth infection may directly suppress the Th1 response, leading to a reduction in virus specific CD8+ cytotoxic T lymphocytes (CTL's) (Allen 1996; Maizels 2003). Plasma HIV-1 viral load is directly related to HIV-1 specific CTL responses in humans and a reduction in CTL response is associated with a more rapid progression of HIV-1 disease (Actor 1993; Gomez-Escobar 2000; Goodridge 2001; Pastrana 1998; van der Kleij 2002). It is plausible that the changes in immune control of HIV-1 replication could lead to more immediate changes in HIV-1 RNA levels following helminth infection or eradication. In contrast, CD4 decline appears more related to immune activation status and changes in regulatory T cell expression and function that may resolve more slowly following treatment of helminth infection (Brown 2006).

The ideal study design to determine anti-helminth treatment effect on HIV-1 progression is a randomized clinical trial. Thus, randomization to immediate versus deferred treatment was used in the single RCT of schistosomiasis eradication. However, the short period of follow-up that is ethically feasible for treatment deferral limits the ability to determine longer-term effects of anti-helminthics on HIV-1 progression. Randomization without determination of helminth-infection status may be an alternative study design to determine if anti-helminthics should be empirically provided for individuals in HIV-1 care programs in areas of high helminth prevalence. This approach does not require helminth screening and may enable determination of helminth treatment effects over longer periods, but would require sufficient helminth prevalence to achieve power to detect effect.

The results of this systematic review suggest there are insufficient data to determine whether de-worming patients with HIV-1 has a beneficial effect on HIV-1 viral load, CD4 count, or clinical progression. There are significant limitations to all of the studies identified and available data do not support empiric anti-helminthic therapy or routine helminth screening of HIV-1 infected individuals. However, the cumulative evidence suggests that de-worming HIV-1 infected individuals may have beneficial effects on plasma HIV-1 RNA viral load. There is a need for large randomized controlled trials with longer follow-up duration in order to assess the impact of de-worming on HIV-1 progression in populations with a high prevalence of both helminth and HIV-1 infection.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Notes
  15. Index terms

 

Implications for practice

Millions of HIV-1-infected individuals are currently living in helminth endemic areas of the world. Given the multiple possible mechanisms by which helminth co-infection may impact the course of HIV-1 infection, it is important to determine if de-worming can reduce HIV-1 disease progression. The potential benefit of de-worming on HIV-1 progression has been evaluated in a single randomized controlled trial and multiple observational studies. Several of these studies have shown a beneficial effect in reducing or attenuating plasma HIV-1 RNA levels, although none has shown a documented clinical benefit or a difference in CD4 decline. While the current evidence suggests that de-worming may have beneficial effects on plasma viral load, available data do not currently support empiric therapy of routine helminth screening of HIV-1 infected individuals.

 
Implications for research

A possible beneficial effect of de-worming on HIV-1 RNA levels has been shown in schistosomiasis and in other helminth co-infections over a short period of follow-up. However, no study conducted to date has evaluated changes in clinical outcomes, CD4 counts, or adverse events over a period of time sufficient to demonstrate meaningful long-term differences. Preliminary evidence suggests that there may be important benefits of de-worming on plasma viral load, which could ultimately slow HIV-1 progression in co-infected individuals. It is important that larger randomized controlled trials with longer follow-up duration assess the impact of de-worming on these outcome measures.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Notes
  15. Index terms

The authors would like to acknowledge Drs Michael Brown, Alison Elliott, and Per Kallestrup for their valuable input and for providing additional unpublished data to include in this review. An earlier version of this review appeared in PLoS Neglected Tropical Diseases (Walson JL, John-Stewart G. Treatment of helminth co-infection in HIV-1 infected individuals: a systematic review of the literature. PLoS Neglected Tropical Diseases. Accepted for publication September 2007).

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Notes
  15. Index terms
Download statistical data

 
Comparison 1. Viral Load
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Change in Log10 HIV-1 RNA after antihelminth treatment or no treament5Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
    1.1 Randomized Controlled Trials
1Std. Mean Difference (IV, Fixed, 95% CI)Not estimable
    1.2 Observational Studies (Helminth uninfected comparator group)
3Std. Mean Difference (IV, Fixed, 95% CI)Not estimable
    1.3 Observational Studies (Participants clearing helminth infection compared to participants without clearance)
3Std. Mean Difference (IV, Fixed, 95% CI)Not estimable

 
Comparison 2. CD4 Count
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Decline in CD4 count after treatment of helminth co-infection4Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
    1.1 Randomized Controlled Trials
1Std. Mean Difference (IV, Fixed, 95% CI)Not estimable
    1.2 Observational Studies (Helminth uninfected comparator group)
3Std. Mean Difference (IV, Fixed, 95% CI)Not estimable
    1.3 Observational Studies (Change in CD4 in the 6 months prior to treatment used as comparator group)
2Std. Mean Difference (IV, Fixed, 95% CI)Not estimable
    1.4 Observational Studies (Participants clearing helminth infection compared to participants without clearance)
2Std. Mean Difference (IV, Fixed, 95% CI)Not estimable

 
Comparison 3. Mortality differences
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Mortality differences between patients treated for helminth infection and helminth uninfected controls3Peto Odds Ratio (95% CI)Totals not selected

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Notes
  15. Index terms

Last assessed as up-to-date: 13 September 2007.

DateEventDescription
12 November 2008AmendedConverted to new review format.


 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Notes
  15. Index terms

Protocol first published: Issue 1, 2007
Review first published: Issue 1, 2008

DateEventDescription
14 September 2007New citation required and conclusions have changedSubstantive amendment


 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Notes
  15. Index terms

None

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Notes
  15. Index terms
 

Internal sources

  • University of Washington, Center for AIDS Research (CFAR), USA.

 

External sources

  • NIH Office of AIDS Research (OAR) for Prevention Science Initiative (PSI), USA.

 

Notes

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Notes
  15. Index terms

This manuscript has been previously published in condensed form in PLoS Neglected Tropical Diseases

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to ongoing studies
  20. Additional references
  21. References to other published versions of this review
Brown 2004 {published and unpublished data}
  • Brown M, Kizza M, Watera C, Quigley MA, Rowland A, Highes P, et al. Helminth infection is not associated iwth faster progression of HIV disease in coinfected adults in Uganda. The Journal of Infectious Diseases 2004;190:1869-79.
Elliott 2003 {published and unpublished data}
  • Elliott AM, Mawwa PA, Joseph S, Namujju PB, Kizza M, Nakiyingi JS, et al. Associations between helminth infection and CD4+ T cell count, viral load and cytokine responses in HIV-1 infected Ugandan adults. Transactions of the Royal Society of Tropical Medicine and Hygiene 2003;97:103-8.
Kallestrup 2005 {published and unpublished data}
  • Kallestrup P, Zinyama R, Gomo E, Butterworth AE, Mudenge B, van Dam GJ, et al. Schistosomiasis and HIV-1 infection in rural Zimbabwe: effect of treatment of schistosomiasis on CD4 cell count and plasma HIV-1 RNA load. The Journal of Infectious Diseases 2005;192:1956-61.
Modjarrad 2005 {published data only}
  • Modjarrad K, Zulu I, Redden DT, Njobvu L, Lane HC, Bentwich Z, Vermund SH. Treatment of intestinal helminths does not reduce plasma concentrations of HIV-1 RNA in coinfected Zambian adults. The journal of infectious diseases 2005;192:1277-83.
Wolday 2002 {published data only (unpublished sought but not used)}
  • Wolday D, Mayaan S, Mariam ZG, Berhe N, Seboxa T, Britton S, Galai N, Landay A, Bentwich Z. Treatment of intestinal worms is associated with decreased HIV plasma viral load. Journal of acquired immune deficiency syndromes 2002;31:56-62.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to ongoing studies
  20. Additional references
  21. References to other published versions of this review
Brown 2005 {published data only}
  • Brown M, Mawa PA, Joseph S, Bukusuba J, Watera C, Whitworth JAG, et al. Treatment of Schistosoma mansoni infection increases helminth-specific type 2 cytokine responses and HIV-1 loads in coinfected Ugandan adults. Journal of Infectious Diseases 2005;191:1648-57.
Gallagher 2005 {published data only}
  • Gallagher M, Malhotra I, Mungai PL, Wamachi AN, Kioko JM, Ouma JH, Muchiri E, King CL. The effects of maternal helminth and malaria infections on mother-to-child HIV transmission. AIDS 2005;19:1849-55.
Ganley-Leal 2006 {published data only}
  • Ganley-Leal LM, Mwinzi PN, Cetre-Sossah CB, Andove J, Hightower AW, Karanja DM, et al. Correlation between eosinophils and protection against reinfection with schistosoma mansoni and the effect of human immunodeficiency virus type 1 coinfection in humans. Infection and Immunity 2006;74(4):2169-76.
Hosseinipour 2007 {published data only}
  • Hosseinipour MC, Napravnik S, Joaki G, Gama S, Mbeye N, Banda B, et al. HIV and parasitic infection and the effect of treatment among adult outpatients in Malawi. The Journal of Infectious Diseases 2007;195:1278-82.
Kallestrup 2006 {published data only}
  • Kallestrup P, Zinyama R, Gomo E, Butterworth AE, van Dam GJ, Gerstoft J, et al. Schistosomiasis and HIV in rural Zimbabwe: efficacy of treatment of schistosomiasis in individuals with HIV coinfection. Clinical Infectious Diseases 2006;42:1781-9.
Kassu 2003 {published data only}
  • Kassu A, Tsegaye A, Wolday D, Petros B, Aklilu M, Fontanet AL, et al. Role of incidental and/or cured intestinal parasitic infections on profile of CD4 and CD8 T cell subsets and activation status in HIV-1 infected and uninfected adult Ethiopians. Clinical Experimental Immunology 2003;132:113-19.
Kelly 1996 {published data only}
  • Kelly P, Lungu F, Keane E, Baggaley R, Kazembe F, Pobee J, et al. Albendazole chemotherapy for treatment of diarrhoea in patients with AIDS in Zambia: a randomized double blind controlled trial. British Medical Journal 1996;312(7040):1187(5).
Lawn 2000 {published data only}
  • Lawn SD, Karanja MS, Mwinzi P, Andove J, Colley DG, Folks TM, et al. The effect of treatment of schistosomiasis on blood plasma HIV-1 RNA concentration in coinfected individuals. AIDS 2000;14(16):2437-43.
McElroy 2005 {published data only}
  • McElroy MD, Elrefaei M, Jones N, Ssali F, Mugyenyi P, Barugahare B, et al. Coinfection with schistosoma mansoni is associated with decreased HIV-specific cytolysis and increased IL-10 production. The Journal of Immunology 2005;174:5119-23.
Mwanakasale 2003 {published data only}
  • Mwanakasale V, Vounatsou P, Sukwa TY, Ziba M, Ernest A, Tanner M. Interactions between schistosoma haematobium and human immunodeficiency virus type 1: The effects of coinfection on treatment outcomes in rural Zambia. American Journal of Tropical Medicine and Hygiene 2003;69(4):420-8.

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to ongoing studies
  20. Additional references
  21. References to other published versions of this review
Actor 1993
  • Actor JK, Shirai M, Kullberg MC, Buller RM, Sher A, Berzofsky JA. Helminth infection results in decreased virus-specific CD8+ cytotoxic T-cell and Th1 cytokine responses as well as delayed virus clearance. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):948-52.
Allen 1996
  • Allen JE, Lawrence RA, Maizels RM. APC from mice harbouring the filarial nematode, Brugia malayi, prevent cellular proliferation but not cytokine production. International immunology. 1996 Jan;8(1):143-51.
Bentwich 1995
  • [8] Bentwich Z, Kalinkovich A, Weisman Z. Immune activation is a dominant factor in the pathogenesis of African AIDS. Immunology today. 1995 Apr;16(4):187-91.
Bentwich 1996
  • Bentwich Z, Weisman Z, Moroz C, Bar-Yehuda S, et al. Immune dysregulation in Ethiopian immigrants in Israel: relevance to helminth infections. Clinical Experimental Immunology 1996;103:239-43.
Borkow 2006
  • Borkow G, Bentwich Z. HIV and helminth co-infection: is deworming necessary? Parasite Immunol. 2006 Nov;28(11):605-12.
Brown 2006
  • Brown M, Mawa PA, Kaleebu P, Elliott AM. Helminths and HIV infection: epidemiological observations on immunological hypotheses. Parasite Immunol. 2006 Nov;28(11):613-23.
Eggena 2005
  • Eggena MP, Barugahare B, Okello M, Mutyala S, Jones N, Ma Y, Kityo C, Mugyenyi P, Cao H. T cell activation in HIV-seropositive Ugandans: differential associations with viral load, CD4+ T cell depletion, and coinfection. The journal of infectious diseases 2005;191:694-701.
Fincham 2003
  • Fincham JE, Markus MB, Adams VJ. Could control of soil-transmitted helminthic infection influence the HIV/AIDS pandemic. Acta Tropica 2003;86:315-333.
Gomez-Escobar 2000
  • Gomez-Escobar N, Gregory WF, Maizels RM. 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. Infect Immun. 2000 Nov;68(11):6402-10.
Goodridge 2001
  • Goodridge HS, Wilson EH, Harnett W, Campbell CC, Harnett MM, Liew FY. Modulation of macrophage cytokine production by ES-62, a secreted product of the filarial nematode Acanthocheilonema viteae. J Immunol. 2001 Jul 15;167(2):940-5.
Gupta 2007
  • Gupta SB, Jacobson LP, Margolick JB, Rinaldo CR, Phair JP, Jamieson BD, et al. Estimating the benefit of an HIV-1 vaccine that reduces viral load set point. The Journal of infectious diseases. 2007 Feb 15;195(4):546-50.
JPT 2005
  • JPT H. Effect measures for continuous outcomes. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005]. The Cochrane Library 2005 [cited 25th May 2007]; Available from: http://www.cochrane.org/resources/handbook/hbook. Available from: http://www.cochrane.org/resources/handbook/hbook.htm.
Lawn 2001
  • Lawn SD, Butera ST, Folks TM. Contribution of immune activation to the pathogenesis and transmission of human immunodeficiency virus type 1 infection. Clinical Microbiology Reviews 2001;14(4):753-777.
Maizels 2003
  • Maizels RM, Yazdanbakhsh M. Immune regulation by helminth parasites: cellular and molecular mechanisms. Nature reviews. 2003 Sep;3(9):733-44.
Pastrana 1998
  • Pastrana DV, Raghavan N, FitzGerald P, Eisinger SW, Metz C, Bucala R, et al. Filarial nematode parasites secrete a homologue of the human cytokine macrophage migration inhibitory factor. Infect Immun. 1998 Dec;66(12):5955-63.
Shapira-Nahor 1998
  • Shapira-Nahor O, Kalinkovich A, Weisman Z, Greenberg Z, Nahmias J, Shapiro M, et al. Increased susceptibility to HIV-1 infection of peripheral blood mononuclear cells from chronically immune-activated individuals. Aids. 1998 Sep 10;12(13):1731-3.
UNAIDS 2004
  • 2004 report on the global AIDS epidemic. 4th global report. UNAIDS 2004.
van der Kleij 2002
  • van der Kleij D, Latz E, Brouwers JF, Kruize YC, Schmitz M, Kurt-Jones EA, et al. A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates toll-like receptor 2 and affects immune polarization. The Journal of biological chemistry. 2002 Dec 13;277(50):48122-9.
Wells et al
  • Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle_Ottawa Scale (NOW) for assessing teh quality of nonrandomized studies in meta-analyses. Department of Epidemiology and Community Medicine, University of Ottawa, Canada. [: http://www.lri.ca/programs/ceu/oxford.htm]

References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to ongoing studies
  20. Additional references
  21. References to other published versions of this review
Walson, in press
  • Walson JL, John-Stewart G. Treatment of helminth co-infection in HIV-1 infected individuals: a systematic review of the literature.. PLoS Neglected Tropical Diseases (In press: accepted for publication September 2007).
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