Treatment of helminth co‐infection in HIV‐1 infected individuals in resource‐limited settings.
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine if treating intestinal parasites (helminths) in individuals with HIV‐1 co‐infection can reduce the progression of HIV‐1 as measured by CD4 count, viral load, or clinical disease progression.
Background
Many individuals living in areas of the world hardest‐hit by the HIV/AIDS epidemic are also infected with a variety of other common infections. Infections such as malaria, tuberculosis, herpes viruses, and intestinal parasites have all been shown to affect the immune system. These infections may have detrimental effects on the host's ability to control the HIV virus in HIV co‐infected individuals (Lawn 2001). Some studies have suggested that these infections may result in a more rapid progression of HIV disease in co‐infected individuals. Co‐infection with other pathogens may lead to a more rapid destruction of the host immune system and potentially to earlier progression to clinical disease and death. Activation of the immune system by these concurrent infections may directly lead to a more rapid destruction of the cells responsible for immunosuppression in HIV‐infected individuals (CD4 cells) (Eggena 2005).
In Africa, there are over 25 million people infected with HIV‐1, and as many as half of these individuals may be co‐infected with soil transmitted parasites, or 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). The role that these infections may play on HIV‐1 replication, progression, and transmission is not clear. Several studies have suggested that helminth co‐infection in HIV‐1‐infected individuals may result in increased levels of HIV‐1 virus in the bloodstream of these individuals, and possibly in more rapid progression of HIV‐1 to the acquired immune deficiency syndrome (AIDS).
In a study of HIV‐1‐infected and uninfected individuals in Ethiopia, helminth co‐infection resulted in increased T‐cell activation. Anti‐helminthic treatment appeared to reduce this 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 also documented a strong association between stool helminth burden and plasma HIV‐1 RNA levels among individuals with helminth co‐infection (p<0.001). In addition, successful treatment of co‐infection (as documented by 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). Following publication of these initial results, several observational studies have shown conflicting results concerning the impact of anti‐helminth therapy on CD4 count, HIV‐1 viral load, and clinical disease progression (Elliott 2004; Gallagher 2005; Modjarrad 2005;).
As treatment programs are introduced into areas where both HIV‐1 and helminth infections are highly prevalent, it is important to determine whether treating helminth co‐infection in patients with HIV‐1 can slow HIV disease progression and/or reduce HIV‐1 transmission. If anti‐helminthic therapy is able to allow HIV‐1‐infected individuals to delay initiation of antiretroviral therapy, or if it is able reduce morbidity and mortality in HIV‐1‐infected individuals, the public health significance of de‐worming HIV‐1‐infected individuals would be substantial.
In this Cochrane review we will evaluate the possibility that treating soil‐transmitted helminths in HIV‐1 co‐infected individuals may impact the progression of HIV‐1 by reducing the amount of HIV virus (HIV‐1 RNA), increasing the immune response against HIV (as measured by CD4 count), or delaying the onset of symptoms of AIDS. While randomized controlled trials would provide the strongest evidence for proving a causal effect of such interventions, observational studies may also provide some evidence.
Objectives
To determine if treating intestinal parasites (helminths) in individuals with HIV‐1 co‐infection can reduce the progression of HIV‐1 as measured by CD4 count, viral load, or clinical disease progression.
Methods
Criteria for considering studies for this review
Types of studies
We will consider randomised or quasi‐randomised controlled trials. If data is insufficient, i.e., no randomised controlled trials (RCT's) are identified, data from observational studies (e.g. cohort, case‐control and cross‐sectional studies) will be considered for inclusion in this review according to the HIV/AIDS Cochrane Review Group policy (HIV CRG). Studies performed in general or specific populations and in both hospitals and/or clinics will be included. Studies performed in any country and published in any language will be included. Studies that rely on historical controls and ecological studies will be excluded, as these provide unreliable data for determining causation and/or association.
Types of participants
We will consider all HIV‐1‐infected individuals with and without documented helminth co‐infection included in studies assessing the association between such helminth co‐infection and HIV‐1 disease progression. Helminths to be included include Schistosomes, Strongyloides, Mansonella, Hookworm, Whipworm, Ascaris, Microfilaria and Trichostrongylus. Included studies will have 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 immuno chromatographic testing methods.
Types of interventions
Interventions
Anti‐helminthic therapy is defined as any pharmaceutical intervention or interventions approved for use in the eradication of soil‐transmitted helminth infection in humans. This includes the benzimidazoles, ivermectin, praziquantel, diethylcarbamazine, bithionol, oxamniquine, pyrantel and nitazoxanide.
Controls
Controls may include another anti‐helminthic drug, a placebo, or no treatment.
Types of outcome measures
The outcome measures to be evaluated are:
Primary:
1) Levels of HIV‐1 RNA.
Secondary:
2) Absolute CD4 count, absolute lymphocyte count, CD8 count and CD4/CD8 ratio
3) Clinical disease progression
4) Adverse events associated with anti‐helminthic therapy will be recorded if reported in the studies.
Search methods for identification of studies
See: HIV/AIDS Group methods used in reviews.
See: Cochrane Review Group search strategy.
We will attempt to identify all relevant studies, regardless of language or publication status (published, unpublished, in press, and in‐progress).
We will search the following databases from 1980 to 2006:
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·Cochrane HIV/AIDS Group Specialized Register (December 2005);
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·Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2005, Issue 4);
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·MEDLINE (1980 to December 2005);
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·EMBASE (1980 to December 2005);
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·AIDSearch(1980 to December 2005);
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·African HealthLine (1993 to December 2005).
We will also scan the reference lists of review articles and included studies to identify further studies. We will contact study authors and other researchers in the field in an attempt to identify additional studies that may be eligible for inclusion in this review.
Data collection and analysis
The titles, abstracts, and descriptor terms of all downloaded material from the electronic searches will be read by JW and GJ and irrelevant reports discarded. All citations identified will then be independently evaluated by JW and GJ to establish relevance of the article according to the pre‐specified criteria. When there is uncertainty as to the relevance of the study, the full article will be obtained.
1. Selection of studies
JW and GJ will independently apply the inclusion criteria. Differences will be resolved by discussion with a third reviewer. Studies will be reviewed for relevance based on study design, types of participants, exposures, and outcome measures. We will seek further information from the authors when papers contain insufficient information to make a decision about eligibility.
Assessment of methodological quality
(a) Allocation concealment
Selection bias will be assessed by the method of generation of allocation sequence and adequacy of allocation concealment.
(b) Blinding
Performance and detection biases will be assessed by checking whether participants, investigators or assessors were blinded.
(c) Inclusion of all randomised participants.
Attrition bias will be assessed by the adequacy of follow up and intention to treat analysis. Trials with loss to follow up £20% will be rated as adequate. They will be rated as inadequate if unclear or above 20%.
If no randomised, controlled trials (RCTs) are identified, assessment of methodological quality for observational trials will be performed as follows:
(i) 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?
(ii) Performance bias
‐ Were assessors of helminth infection status blinded to HIV status?
‐ Was the same method of ascertainment used in cases and controls?
(iii) Detection bias
‐ Was helminth infection status ascertained by microscopy, culture and/or immunologic testing?
‐ Was HIV status ascertained using an ELISA test, Western blot, or particle agglutination test?
‐ Was HIV status confirmed using a different or second test from this list?
‐ Were assessors of HIV status blinded to helminth infection status (or were HIV and helminth testing done in independent laboratories)?
(iv) 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 suggestive of bias?
(v) Selection bias
‐ Were cases selected from the general population?
‐ Were controls selected from the same population as the cases?
(vi) Control of confounding
‐ The following factors are pre‐specified by the review team as potential confounders. The authors (JW and GJ) will assess whether they are demonstrated to be similar in both groups, matched in the design or adjusted for in the analysis.
·age at baseline
·study location (urban/rural, vicinity to fresh water sources with known high burden of parasites)
·education, occupation, socio‐economic status
·marital status
If observational studies are included, the methodological quality of the included cohort, case‐control and cross‐sectional studies will be evaluated independently by JW and GJ. Reviewers will not be blinded to the names of the authors, institutions, journals of publication, or results of the studies.
2. Data extraction
Data will be independently extracted by JW and GJ. Standardized data extraction forms will be used. A separate form will be usedSYMBOL 45 \f "Symbol" \s 9one for randomized trials, one for cohort/cross‐sectional studies, and one for case‐control studies (if necessary).
Analysis
Meta‐analysis will be conducted if data allows and where appropriate. If data does not permit meta‐analysis, a narrative synthesis will be performed. Where appropriate, we will collect each dichotomous outcome for effect in terms of risk ratio with a 95% confidence interval. Continuous outcomes may be assessed with a weighted mean difference (WMD) and 95% confidence interval. If and where appropriate, and after careful consideration of the degree of heterogeneity between trials, we may statistically pool the outcomes and examine the differences between fixed and random effects models. We plan to perform a sensitivity analysis on results to look at the possible contribution of differences in methodological quality, trials of high quality compared to all included trials to examine the stability.
We will assess heterogeneity by checking for overlapping of confidence interval in the forest plot, test with Cochrane Q test with p‐value <0.1 and I2 test with value >70% as significant. Where appropriate, and after careful consideration of the degree of heterogeneity between studies, we will statistically pool the outcomes. We will further explore heterogeneity by conducting subgroup analyses if there is a sufficient number of trials of adequate size. Ability to conduct subgroup analyses will also depend on whether or not the required information is recorded in the trial publications. Possible subgroups include:
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·age (children and adults);
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·type and intensity of helminth infection;
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·class of anti‐helminthic;
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·duration of follow up.
