Antihelminthics in helminth‐endemic areas: effects on HIV disease progression

Arianna Rubin Means; Paul Burns; David Sinclair; Judd L Walson

doi:10.1002/14651858.CD006419.pub4

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Figure 1

Study flow diagram.

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Figure 2

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included trial.

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Figure 3

'Risk of bias' graph: review authors' judgements about each methodological quality item presented as percentages across all included trials.

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Comparison 1 Deworming drugs versus placebo in people with unknown helminth infection status, Outcome 1 Viral load: change in log10 HIV‐1 RNA.

Analysis 1.1

Comparison 1 Deworming drugs versus placebo in people with unknown helminth infection status, Outcome 1 Viral load: change in log₁₀ HIV‐1 RNA.

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Analysis 1.2

Comparison 1 Deworming drugs versus placebo in people with unknown helminth infection status, Outcome 2 Change in CD4 count.

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Comparison 2 Deworming drugs versus placebo in people with confirmed helminth infection, Outcome 1 Viral load: change in log10 HIV‐1 RNA.

Analysis 2.1

Comparison 2 Deworming drugs versus placebo in people with confirmed helminth infection, Outcome 1 Viral load: change in log₁₀ HIV‐1 RNA.

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Analysis 2.2

Comparison 2 Deworming drugs versus placebo in people with confirmed helminth infection, Outcome 2 Change in CD4 count.

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Comparison 3 Deworming drugs versus placebo; all trials, Outcome 1 Change in log10 HIV RNA, by antihelminthic.

Analysis 3.1

Comparison 3 Deworming drugs versus placebo; all trials, Outcome 1 Change in log₁₀ HIV RNA, by antihelminthic.

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Analysis 3.2

Comparison 3 Deworming drugs versus placebo; all trials, Outcome 2 Difference in adverse events between treatment and no treatment groups.

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Analysis 3.3

Comparison 3 Deworming drugs versus placebo; all trials, Outcome 3 Difference in mortality events between treatment and no treatment groups.

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Summary of findings for the main comparison. Summary of findings for participants with unknown helminth infection status

Deworming drugs compared with placebo for people with HIV and an unknown helminth infection status
Participant or population: HIV‐positive people Settings: urban and rural areas co‐endemic for helminths and HIV Intervention: deworming drugs (albendazole or praziquantel or a combination) Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Number of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Placebo	Deworming drugs
Viral load	At 6 weeks after a single dose		166 (1 trial)	⊕⊕⊝⊝^1,2,3,4 low
	in the control group, the mean change in viral load was an increase of 0.09 log₁₀ viral RNA	On average, with deworming, there was a suppressive effect on mean viral load of 0.14 log₁₀ viral RNA (0.35 benefit to 0.07 harm)
	At 2 years after multiple doses		917 (1 trial)	⊕⊕⊕⊝^1,2,5,6 moderate
	In the control group, the mean viral load increased by 0.03 log₁₀ viral RNA	On average, with deworming, there was a suppressive effect on mean viral load of 0.01 log₁₀ viral RNA (0.03 benefit to 0.05 harm)
CD4+ cell count	At 2 years after multiple doses		917 (1 trial)	⊕⊕⊝⊝^1,2,4,5 low
	In the control group, the mean CD4+ cell count reduced by 37.3 CD4+ cells/µL	On average, with deworming, there was a favourable effect on mean CD4+ cell count of 2.60 CD4+ cells/µL (15.35 benefit 10.15 harm)
The basis for the assumed risk* (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: CI: confidence interval; RR: risk ratio; RNA: ribonucleic acid; HIV: human immunodeficiency virus.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
¹No serious risk of bias: this single trial was at low risk of selection bias. ²No serious inconsistency: this was not applicable as there was only a single trial. ³We downgraded by 1 for serious indirectness: this single trial is based upon a specific sample of pregnant women treated with albendazole or praziquantel, or both. The overall finding of an effect cannot be easily generalized to all populations or settings. ⁴We downgraded by 1 for imprecision: the 95% CI includes potentially clinically important differences as well as no effect. Further larger studies are needed. ⁵We downgraded by 1 for serious indirectness: this trial was conducted in three sites in rural and urban Kenya. Helminth infection was expected to be high but was not assessed at baseline. The findings are not easily generalized to all helminth endemic settings. ⁶No serious imprecision: the 95% CI includes no effect but is narrow around the estimate and excludes clinically important differences.

Summary of findings for the main comparison. Summary of findings for participants with unknown helminth infection status

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Summary of findings 2. Summary of findings for participants with confirmed helminth infections

Deworming drugs compared with placebo for people with HIV and confirmed helminth infections
Participant or population: HIV‐positive people with proven helminth infection Settings: urban and rural areas co‐endemic for helminths and HIV Intervention: deworming drugs (albendazole, praziquantel, albendazole and praziquantel, or diethylcarbamazine) Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Number of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Placebo	Deworming drugs
Viral load	At 6 to 12 weeks		445 (4 trials)	⊕⊕⊝⊝ low^1,2,3,4
	In the control groups, the mean change in viral load ranged from a 0.13 decrease to an increase of 0.21 log₁₀ viral RNA	On average, with deworming, there was a small suppressive effect on mean viral load of 0.13 log₁₀ viral RNA (0.26 benefit to 0.00 benefit)
CD4+ cell count	At 6 to 12 weeks		358 (3 trials)	⊕⊕⊝⊝ low^2,5,6,7
	In the control groups, the mean change in CD4+ cell count ranged from a decrease of 68 to an increase of 45 CD4+ cells/µL	On average, with deworming, there was favourable effect on mean CD4+ cell count of 37.86 CD4+ cells/µL (7.36 benefit to 68.35 benefit)
The basis for the assumed risk* (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: CI: confidence interval; RR: risk ratio; RNA: ribonucleic acid; HIV: human immunodeficiency virus.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
¹We downgraded by 1 for serious risk of bias: of the five studies, only one had CIs that excluded the possibility of no effect and this study was at high risk of selection bias. ²No serious inconsistency: statistical heterogeneity was low. ³We downgraded by 1 for serious indirectness: the only trial for which the CIs excluded the possibility of no effect administered praziquantel to people with schistosomiasis. The overall finding of an effect cannot be easily generalized to all deworming drugs, helminth infections, or settings. ⁴No serious imprecision: the overall 95% CI is wide and includes both clinically important effects and no effect. However, as potential harm is excluded, we did not further downgrade the evidence. ⁵No serious risk of bias: one trial was at high risk of selection bias, but excluding this trial did not substantially change the result. ⁶We downgraded by 1 for serious indirectness: the included trials are from a very limited number of settings and participants. The overall finding is not easily generalized to all deworming drugs, helminth infections, or settings, and further trials are needed. ⁷We downgraded by 1 for imprecision: the 95% CI is wide and includes potentially clinically important differences as well as no effect. Further larger studies are needed.

Summary of findings 2. Summary of findings for participants with confirmed helminth infections

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Summary of findings 3. Summary of findings for secondary outcomes

Deworming drugs compared with placebo for people with HIV and both known and unknown helminth infection status
Participant or population: HIV‐positive people Settings: urban and rural areas co‐endemic for helminths and HIV Intervention: deworming drugs (albendazole, praziquantel, albendazole and praziquantel, or diethylcarbamazine) Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Placebo	Albendazole
Iron deficiency (serum ferritin)	log₁₀ mean increase of 0.04 µg/L	log₁₀ mean increase of 0.07 µg/L	Deworming drugs associated with a 0.03 higher µg/L log₁₀ mean ferritin measure (0.30 lower to 0.35 higher)	16 (1 trial)	⊕⊝⊝⊝^1,2,3,4 very low
Anaemia (serum haemoglobin)	Increase in 0.15 g/dL	Decrease in 0.10 g/dL	Deworming drugs associated with a 0.25 lower g/dL haemoglobin (0.58 lower to 0.08 higher)	130 (1 trial)	⊕⊝⊝⊝^2,4,5,6 very low
Mortality	41 per 1000	52 per 1000	RR 0.77 (0.52 to 1.14)	1627 (5 trials)	⊕⊕⊝⊝^7,8,9,10 low
Adverse events	32 per 1000	35 per 1000	RR 1.23 (0.53 to 2.83)	1649 (7 trials)	⊕⊝⊝⊝^4,9,11,12 very low
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: CI: confidence interval; RR: risk ratio; HIV: human immunodeficiency virus.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
¹No serious risk of bias: this single trial was at risk of selection bias. However, the outcome is an objective laboratory measure. We did not downgrade the quality of the evidence. ²No serious inconsistency: not applicable as this is a single trial. ³We downgraded by 2 for serious indirectness: this single trial is based upon a very small sample size of people treated with diethylcarbamazine for lymphatic filariasis. The overall finding of an effect can not be easily generalized to all deworming drugs, helminth infections, or settings. ⁴We downgraded by 1 for imprecision: the 95% CI is wide and includes potentially clinically important differences as well as no effect. Larger studies are needed. ⁵We downgraded by 1 for serious risk of bias: this single trial was at high risk of selection bias. ⁶Downgraded by 1 for serious indirectness: this single trial is based upon a very small sample size of people treated with praziquantel for schistosomiasis. The overall finding of an effect can not be easily generalized to all deworming drugs or helminth infections or settings. ⁷No serious risk of bias: although some of the trials are at risk of selection bias the outcome is an objective measure. We did not downgrade the evidence. ⁸No serious inconsistency: statistical heterogeneity was low. ⁹No serious indirectness: these trials took place in different settings, with different drugs, and with different helminth infections present. However, effects of treatment were consistent across the trials. ¹⁰We downgraded by 2 for imprecision: the 95% CI is wide and includes potentially clinically important differences as well as no effect. Additionally the trials were not powered to detect changes in the rare outcome of mortality. A trial in which 3% of controls died would require a sample size of 7648 participants to attain 80% power to detect a 33% reduction in mortality. ¹¹We downgraded by 2 for serious risk of bias: it is unclear how some of the trial authors defined adverse events and thus there is risk of bias in outcome assessment. ¹²No serious inconsistency: however, the analysis has an I² statistic value of 34%, which may represent low to moderate heterogeneity.

Summary of findings 3. Summary of findings for secondary outcomes

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Table 1. Cochrane librarian search strategy for MEDLINE

Number	Search terms
#1	Search (HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tiab] OR hiv‐1[tiab] OR hiv‐2[tiab] OR hiv1[tiab] OR hiv2[tiab] OR hiv infect[tiab] OR human immunodeficiency virus[tiab] OR human immunedeficiency virus[tiab] OR human immuno‐deficiency virus[tiab] OR human immune‐deficiency virus[tiab] OR ((human immun[tiab]) AND (deficiency virus[tiab])) OR acquired immunodeficiency syndrome[tiab] OR acquired immunedeficiency syndrome[tiab] OR acquired immuno‐deficiency syndrome[tiab] OR acquired immune‐deficiency syndrome[tiab] OR ((acquired immun*[tiab]) AND (deficiency syndrome[tiab])) OR "sexually transmitted diseases, Viral"[MeSH:NoExp]))
#2	Search (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh])
#3	Search (helminths[mh] OR helminth[tiab] OR nematode[tiab] OR worm[tiab] OR parasites[mh] OR parasit[tiab] OR round worm[tiab] OR roundworm[tiab] OR hookworm[tiab] OR hook worm[tiab] OR ancylostoma[tiab] OR cestode[tiab] OR tapeworm[tiab] OR tape worm[tiab] OR trematode[tiab] OR fluke[tiab] OR whipworm[tiab] OR whip worm[tiab] OR trichuris[tiab] OR ascaris[tiab] OR enterobi[tiab] OR strongyloide[tiab] OR mansonell[tiab] OR taenia[tiab] schistosom[tiab] OR necator[tiab] OR paragonim[tiab] OR hymenolepis[tiab] OR fasciol[tiab] OR filariasis[tiab] OR trichostrongl[tiab] OR microfilaria[tiab] OR parasitic diseases[mh:noexp] OR helminthiasis[mh] OR intestinal diseases, parasitic[mh])
#4	Search (benzimidazoles OR albendazole OR mebendazole OR ivermectin OR praziquantel OR diethylcarbamazine OR bithionol OR oxamniquine OR pyrantel OR nitazoxanide OR anthelmintic OR anthelmintics OR anthelminthic OR anthelminthics OR “anti helminthic” OR “anti helminthics” OR “anti helmintic” OR “anti helmintics” OR antihelminthic OR antihelminthics OR antihelmintic OR antihelmintics)
#5	Search (#1 AND #2 AND #3 AND #4)
#6	Search (((#1 AND #2 AND #3 AND #4))) AND ("1980/01/01"[Date ‐ Publication] : "2015/09/29"[Date ‐ Publication])

Table 1. Cochrane librarian search strategy for MEDLINE

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Table 2. Cochrane librarian search strategy for EMBASE

Number	Search terms
#1	'human immunodeficiency virus infection' exp OR 'human immunodeficiency virus infection':ab,ti OR 'hiv infection':ab,ti OR 'hiv infections':ab,ti OR 'human immunodeficiency virus'/exp OR 'human immunodeficiency virus':ab,ti OR hiv:ab,ti OR 'hiv 1':ab,ti OR 'hiv 2':ab,ti OR 'human immune deficiency virus':ab,ti OR 'human immuno deficiency virus':ab,ti OR 'acquired immunodeficiency syndrome':ab,ti OR 'acquired immuno deficiency syndrome':ab,ti OR 'acquired immune deficiency syndrome':ab,ti OR 'acquired immunedeficiency syndrome':ab,ti
#2	'randomized controlled trial'/de OR 'randomized controlled trial' OR random:ab,ti OR trial:ti OR allocat:ab,ti OR factorial:ab,ti OR placebo:ab,ti OR assign:ab,ti OR volunteer:ab,ti OR 'crossover procedure'/de OR 'crossover procedure'OR 'double‐blind procedure'/de OR 'double‐blind procedure' OR 'single‐blind procedure'/de OR 'single‐blind procedure' OR (doublNEAR/3 blind):ab,ti OR (singl:ab,ti AND blind:ab,ti) OR crossover:ab,ti OR cross+over:ab,ti OR (crossNEXT/1 over*):ab,ti
#3	'animal'/de OR 'animal experiment'/de OR 'invertebrate'/de OR 'animal tissue'/de OR 'animal cell'/de OR 'nonhuman'/de
#4	'human'/de OR 'normal human'/de OR 'human cell'/de
#5	#3 AND #4
#6	#3 NOT #5
#7	#2 NOT #6
#8	'helminth'/exp OR helminth:ab,ti OR nematode:ab,ti OR worm:ab,ti OR 'parasite'/exp OR parasit:ab,ti OR roundAND worm:ab,ti OR roundworm:ab,ti OR hookworm:ab,ti OR hookAND worm:ab,ti OR ancylostoma:ab,ti OR cestode:ab,ti OR tapeworm:ab,ti OR tapeAND worm:ab,ti OR trematode:ab,ti OR fluke:ab,ti OR whipworm:ab,ti OR whipAND worm:ab,ti OR trichuris:ab,ti OR ascaris:ab,ti OR enterobi:ab,ti OR strongyloide:ab,ti OR mansonell:ab,ti OR taenia:ab,ti AND schistosom:ab,ti OR necator:ab,ti OR paragonim:ab,ti OR hymenolepis:ab,ti OR fasciol:ab,ti OR filariasis:ab,ti OR trichostrongl:ab,ti OR microfilaria:ab,ti OR 'parasitic diseases'/exp OR 'helminthiasis'/de OR 'intestine infection'/de
#9	'benzimidazoles'/de OR benzimidazolesOR 'albendazole'/de OR albendazoleOR 'mebendazole'/de OR mebendazoleOR 'ivermectin'/de OR ivermectinOR 'praziquantel'/de OR praziquantelOR 'diethylcarbamazine'/de OR diethylcarbamazineOR 'bithionol'/de OR bithionolOR 'oxamniquine'/de OR oxamniquineOR 'pyrantel'/de OR pyrantelOR 'nitazoxanide'/de OR nitazoxanideOR 'anthelmintic'/de OR anthelminticOR 'anthelmintics'/de OR anthelminticsOR 'anthelminthic'/de OR anthelminthicOR anthelminthicsOR 'anti helminthic'OR 'anti helminthics'OR 'anti helmintic'OR 'anti helmintics'OR antihelminthicOR antihelminthicsOR 'antihelmintic'/de OR antihelminticOR 'antihelmintics'/de OR antihelmintics
#10	#1 AND #7 AND #8 AND #9
#11	#1 AND #7 AND #8 AND #9 AND [1‐1‐1980]/sd NOT [29‐09‐2015]/sd

Table 2. Cochrane librarian search strategy for EMBASE

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Table 3. Cochrane librarian search strategy for CENTRAL

Number	Search terms
#1	MeSH descriptor: [HIV Infections] explode all trees
#2	MeSH descriptor: [HIV] explode all trees
#3	hiv or hiv‐1* or hiv‐2* or hiv1 or hiv2 or (hiv near infect) or (human immunodeficiency virus) or (human immunedeficiency virus) or (human immune‐deficiency virus) or (human immuno‐deficiency virus) or (human immune deficiency virus) or (human immuno 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) (Word variations have been searched)
#4	MeSH descriptor: [Lymphoma, AIDS‐Related] this term only
#5	MeSH descriptor: [Sexually Transmitted Diseases, Viral] this term only
#6	#1 or #2 or #3 or #4 or #5
#7	[mh helminths] or helminth:ti,ab,kw or meatode:ti,ab,kw or worm:ti,ab,kw or [mh parasites] or parasit:ti,ab,kw or round worm:ti,ab,kw or roundworm:ti,ab,kw or hook worm:ti,ab,kw or hookworm:ti,ab,kw or ancylostoma:ti,ab,kw or cestode:ti,ab,kw or tapeworm:ti,ab,kw or tape worm:ti,ab,kw or trematode:ti,ab,kw or fluke:ti,ab,kw or whipworm:ti,ab,kw or whip worm:ti,ab,kw or trichuris:ti,ab,kw or ascaris:ti,ab,kw or enterobi:ti,ab,kw or strongyloide:ti,ab,kw or mansonell:ti,ab,kw or taenia:ti,ab,kw schistosom:ti,ab,kw or necator:ti,ab,kw or paragonim:ti,ab,kw or hymenolepis:ti,ab,kw or fasciol:ti,ab,kw or filariasis:ti,ab,kw or trichostrongl:ti,ab,kw or microfilaria:ti,ab,kw or [mh ^"parasitic diseases"] or [mh helminthiasis] or [mh ^"intestinal diseases, parasitic"] (Word variations have been searched)
#8	benzimidazoles or albendazole or mebendazole or ivermectin or praziquantel or diethylcarbamazine or bithionol or oxamniquine or pyrantel or nitazoxanide or anthelmintic or anthelmintics or anthelminthic or anthelminthics or "anti helminthic" or "anti helminthics" or "anti helmintic" or "anti helmintics" or antihelminthic or antihelminthics or antihelmintic or antihelmintics (Word variations have been searched)
#9	#6 and #7 and #8 Publication Year from 1980 to 2015, in Trials

Table 3. Cochrane librarian search strategy for CENTRAL

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Table 4. Cochrane librarian search strategy for the WHO ICTRP

Number	Search terms
#1	HIV AND HELMINTH

Table 4. Cochrane librarian search strategy for the WHO ICTRP

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Table 5. Cochrane librarian search strategy for clinicaltrials.gov

Number	Search terms
#1	HIV AND HELMINTH \| Interventional Studies \| received from 01/01/1980 to 09/29/2015

Table 5. Cochrane librarian search strategy for clinicaltrials.gov

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Table 6. Search terms used in 2009 newly applied in MEDLINE

Number	Search terms
#1	“HIV Infections”[MeSH] OR “HIV”[MeSH] OR hiv [tw] OR hiv‐1[tw] OR hiv‐2[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immunodeficiency 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 immunodeficiency syndrome[tw] OR acquired immune‐deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR “Sexually Transmitted Diseases, Viral”[MeSH:NoExp]
#2	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])
#3	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 STRONGYLOIDES OR ANCYLOSTOMA OR ANCYLOSTOMAS OR NECATOR OR NECATORS OR HYMENOLEPIS OR PARAGONIMUS OR FASCIOLA OR TAENIA 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 SCHISTOSOMIASIS OR MANSONELLA OR FILARIASIS OR MICROFILARIA OR TRICHOSTRONGYLUS OR TRICHOSTRONGYLOSIS OR STRONGYLOIDEA OR PARAGONIMIASIS
#4	BENZIMIDAZOLES OR ALBENDAZOLE OR MEBENDAZOLE OR IVERMECTIN OR PRAZIQUANTEL OR DIETHYLCARBAMAZINE OR BITHIONOL OR OXAMNIQUINE OR PYRANTEL OR NITAZOXANIDE
#5	#3 AND #4
#6	#1 AND #2 AND #5
#7	#1 AND #2 AND #5 Limits: Publication Date from 1980 to 2015/09/29

Table 6. Search terms used in 2009 newly applied in MEDLINE

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Table 7. Search terms used in 2009 newly applied in EMBASE

Number	Search terms
#1	((’human immunodeficiency virus infection’/exp OR ’human immunodeficiency virus infection’) OR (’human immunodeficiency virus infection’/exp OR ’human immunodeficiency virus infection’)) OR ((’human immunodeficiency virus’/exp OR ’human immunodeficiency virus’) OR (’human immunodeficiency virus’/exp OR ’human immunodeficiency virus’)) OR (hiv:ti OR hiv:ab) OR (’hiv‐1’:ti OR ’hiv‐1’:ab) OR (’hiv‐2’:ti OR ’hiv‐2’:ab) OR (’human immunodeficiency virus’:ti OR ’human immunodeficiency virus’:ab) OR (’human immuno‐deficiency virus’:ti OR ’human immuno‐deficiency 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 (’acquired immune‐deficiency syndrome’:ti OR ’acquired immune‐deficiency syndrome’:ab) OR (’acquired immunedeficiency syndrome’:ti OR ’acquired immunedeficiency syndrome’:ab) OR (’acquired immunodeficiency syndrome’:ti OR ’acquired immunodeficiency syndrome’:ab) OR (’acquired immuno‐deficiency syndrome’:ti OR ’acquired immuno‐deficiency 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 (double:ti AND blind:ti) OR (doubl:ab AND blind:ab) OR (single:ti AND blind:ti) OR (single:ab AND blind:ab) OR assign:ti OR assign:ab OR allocat:ti OR allocate:ab OR volunteer:ti OR volunteer:ab OR 'crossover procedure'/exp OR 'crossover procedure' OR 'double‐blind procedure'/exp OR 'double‐blind procedure' OR 'single‐blind procedure'/exp OR 'single‐blind procedure' OR 'randomized controlled trial'/exp OR 'randomized controlled trial'
#3	'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 'taenia' 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' OR trichostronglylosis OR stronglyloidea OR pargonimiasis
#4	((’benzimidazoles’/exp OR ’benzimidazoles’) OR (’benzimidazoles’/exp OR ’benzimidazoles’)) OR ((’albendazole’/exp OR ’albendazole’) OR (’albendazole’/exp OR ’albendazole’)) OR ((’mebendazole’/exp OR ’mebendazole’) OR (’mebendazole’/exp OR ’mebendazole’)) OR ((’ivermectin’/exp OR ’ivermectin’) OR (’ivermectin’/exp OR ’ivermectin’)) OR ((’praziquantel’/exp OR ’praziquantel’) OR (’praziquantel’/exp OR ’praziquantel’)) OR ((’diethylcarbamazine’/exp OR ’diethylcarbamazine’) OR (’diethylcarbamazine’/exp OR ’diethylcarbamazine’)) OR ((’bithionol’/exp OR ’bithionol’) OR (’bithionol’/exp OR ’bithionol’)) OR ((’oxamniquine’/exp OR ’oxamniquine’) OR (’oxamniquine’/exp OR ’oxamniquine’)) OR ((’pyrantel’/exp OR ’pyrantel’) OR (’pyrantel’/exp OR ’pyrantel’)) OR ((’nitazoxanide’/exp OR ’nitazoxanide’) OR (’nitazoxanide’/exp OR ’nitazoxanide’))
#5	#3 OR #4
#6	#1 AND #2 AND #5 [1‐1‐1980]/sd NOT [29‐09‐2015]/sd

Table 7. Search terms used in 2009 newly applied in EMBASE

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Table 8. Search terms used in 2009 newly applied in CENTRAL

Number	Search terms
#1	(HIV INFECTIONS) OR HIV OR HIV OR HIV‐1* OR HIV‐2* OR HIV1 OR HIV2 OR (HIV INFECT) OR (HUMAN IMMUNODEFICIENCY VIRUS) OR (HUMAN IMMUNEDEFICIENCY VIRUS) OR (HUMAN IMMUNO‐DEFICIENCY VIRUS) OR (HUMAN IMMUNE‐DEFICIENCY VIRUS) OR ((HUMAN IMMUN) AND (DEFICIENCY VIRUS)) OR (ACQUIRED IMMUNODEFICIENCY SYNDROME) OR (ACQUIRED IMMUNEDEFICIENCY SYNDROME) OR (ACQUIRED IMMUNO‐DEFICIENCY SYNDROME) OR (ACQUIRED IMMUNE‐DEFICIENCY SYNDROME) OR ((ACQUIRED IMMUN*) AND (DEFICIENCY SYNDROME)) OR (VIRAL SEXUALLY TRANSMITTED DISEASES)
#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 CES‐TODES 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 STRONGYLOIDES OR ANCYLOSTOMA OR ANCYLOSTOMAS OR NECATOR OR NECATORS OR HYMENOLEPIS OR PARAGONIMUS OR FASCIOLA OR TAENIA 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 SCHISTOSOMIASIS OR MANSONELLA OR FILARIASIS OR MICROFILARIA OR TRICHOSTRONGYLUS OR TRICHOSTRONGYLOSIS OR STRONGYLOIDEA OR PARAGONIMIASIS
#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 from 1980 to 2015

Table 8. Search terms used in 2009 newly applied in CENTRAL

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Table 9. Search terms used in 2009 newly applied in AIDSEARCH

Number	Search terms
#1	(HIV INFECTIONS) OR HIV OR HIV OR HIV‐1* OR HIV‐2* OR HIV1 OR HIV2 OR (HIV INFECT) OR (HUMAN IMMUNODEFICIENCY VIRUS) OR (HUMAN IMMUNEDEFICIENCY VIRUS) OR (HUMAN IMMUNO‐DEFICIENCY VIRUS) OR (HUMAN IMMUNE‐DEFICIENCY VIRUS) OR ((HUMAN IMMUN) AND (DEFICIENCY VIRUS)) OR (ACQUIRED IMMUNODEFICIENCY SYNDROME) OR (ACQUIRED IMMUNEDEFICIENCY SYNDROME) OR (ACQUIRED IMMUNO‐DEFICIENCY SYNDROME) OR (ACQUIRED IMMUNE‐DEFICIENCY SYNDROME) OR ((ACQUIRED IMMUN*) AND (DEFICIENCY SYNDROME)) OR (SEXUALLY TRANSMITTED DISEASES, VIRAL)
#2	((RANDOMIZED CONTROLLED TRIAL) OR (CONTROLLED CLINICAL TRIAL) OR (RANDOMIZED CONTROLLED TRIALS) OR (RANDOM ALLOCATION) OR (DOUBLE‐BLIND METHOD) OR (SINGLE‐ BLIND METHOD) OR (CLINICAL TRIAL) OR (CLINICAL TRIALS) OR (“CLINICAL TRIAL”) OR ((SINGL* OR DOUBL* OR TREBL* OR TRIPL* AND (MASK* OR BLIND)) OR PLACEBOS OR PLACEBO OR RANDOM* OR (COMPARATIVE STUDY) OR (EVALUATION STUDIES) OR (FOLLOW‐UP STUDIES) OR (PROSPECTIVE STUDIES) OR CONTROL* OR PROSPECTIV* OR VOLUNTEER*)) NOT (ANIMALS NOT HUMAN)
#3	#1 AND #2
#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 CES‐TODES 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 STRONGYLOIDES OR ANCYLOSTOMA OR ANCYLOSTOMAS OR NECATOR OR NECATORS
#5	HYMENOLEPIS OR PARAGONIMUS OR FASCIOLA OR TAENIA 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 SCHISTOSOMIASIS OR MANSONELLA OR FILARIASIS OR MICROFILARIA OR TRICHOSTRONGYLUS OR TRICHOSTRONGYLOSIS OR STRONGYLOIDEA OR PARAGONIMIASIS
#6	BENZIMIDAZOLES OR ALBENDAZOLE OR MEBENDAZOLE OR IVERMECTIN OR PRAZIQUANTEL OR DIETHYLCARBAMAZINE OR BITHIONOL OR OXAMNIQUINE OR PYRANTEL OR NITAZOXANIDE
#7	#4 OR #5 OR #6
#8	#7 AND #3

Table 9. Search terms used in 2009 newly applied in AIDSEARCH

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Table 10. Search strategy for the WHO Global Health Library

Number	Search terms
#1	Helminth* AND "HIV Infections" received from 01/01/1980 to 09/29/2015

Table 10. Search strategy for the WHO Global Health Library

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Table 11. Characteristics of trials in which participants had unknown helminth infection status

Trial	Country	Setting	Year enrolment completed	Inclusion criteria	Age	Total randomized	Number HIV‐positive participants	Taking ART	Number co‐infected with helminths at baseline
Kelly 1996 ZMB	Zambia	Urban	Not stated	HIV‐infected adults with persistent diarrhoea	> 18 years	174	174	Not stated (probably low)	Unknown
Webb 2012 UGA	Uganda	Urban	2005	HIV‐infected pregnant women	Not stated	264	264	< 3%	67% had at least 1 helminth species
Walson 2012 KEN	Kenya	Urban/rural	2011	HIV‐infected, not on ART	> 18 years	948	948	None at baseline	Unknown
Abbreviations: HIV: human immunodeficiency virus; ART: antiretroviral.

Table 11. Characteristics of trials in which participants had unknown helminth infection status

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Table 12. Description of interventions

Trial	Intervention			Control	Outcomes	Timing
Trial	Drug	Dose	Frequency	Control	Outcomes	Timing
Walson 2008 KEN	Albendazole	400 mg	Once daily for 3 days	Placebo	Viral load CD4 Adverse events Mortality events	12 weeks
Abate 2014 ETH	Albendazole	400 mg	Once daily for 3 days	Placebo	CD4 Adverse events Mortality events	12 weeks
Kallestrup 2005 ZWE	Praziquantel	40 mg/kg	Once only	No intervention	Viral load CD4	12 weeks
Nielsen 2007 TZA	Diethylcarbamazine	6 mg/kg	Once only	Placebo	Viral load CD4 Adverse events	12 weeks
Kelly 1996 ZMB	Albendazole	800 mg	Twice daily for 14 days	Placebo	Adverse events Mortality events	6 months
Suputtamongkol 2011 THA	Ivermectin	200 mg/kg	Single or double dose 2 weeks apart	Albendazole	Adverse events	1 year
Webb 2012 UGA	Albendazole Praziquantel	400 mg 40 mg/kg	Once only Once only	Placebo	Viral load Adverse events Mortality events	6 weeks
Walson 2012 KEN	Albendazole Praziquantel	400 mg 25 mg/kg	Every 3 months Annually	No intervention	Viral load CD4 Adverse events Mortality events	2 years

Table 12. Description of interventions

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Table 13. Characteristics of trials in which participants had confirmed helminth infections

Trial	Country	Setting	Year enrolment completed	Inclusion criteria	Age	Total randomized	Number of HIV‐positive participants	Taking ART	Number co‐infected with helminths at baseline
Walson 2008 KEN	Kenya	Urban/rural	2007	HIV‐infected with at least one helminth co‐infection	> 18 years	234	234	None at baseline	All
Abate 2014 ETH	Ethiopia	Urban	2012	Newly diagnosed TB participants with helminth co‐infection	15 to 60 years	140	32	94% of intervention group, 100% of controls	All
Kallestrup 2005 ZWE	Zimbabwe	Rural	2003	Adults infected with schistosomiasis	> 18 years	287	130	Not stated	All
Nielsen 2007 TZA	Tanzania	Rural	2002	HIV‐infected adults	22 to 70 years	34	34	Not stated	18
Suputtamongkol 2011 THA	Thailand	Urban	2009	Adults with characteristic strongyloides infection	> 18 years	100	10	Not stated	All
Abbreviations: HIV: human immunodeficiency virus; ART: antiretroviral; TB: tuberculosis.

Table 13. Characteristics of trials in which participants had confirmed helminth infections

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Table 14. Ongoing or planned RCTs

Trial name	Relevant intervention	Relevant outcome	Target population	Location(s)	Estimated completion date
Reduction of EArly mortaLITY in HIV‐infected Adults and Children Starting Antiretroviral Therapy (REALITY)	Immediate enhanced opportunistic infections (OI) prophylaxis with isoniazid/pyridoxine and cotrimoxazole, plus 12 weeks fluconazole, 5 days azithromycin, and a single dose of albendazole versus cotrimoxazole prophylaxis alone for the first 12 weeks followed by isoniazid and any prophylaxis and/or treatment prescribed at screening	• Change in CD4 count • Adverse events	HIV‐infected individuals ages ≥ 5 years	Kenya, Malawi, Uganda, Zimbabwe	February 2016
Can Anthelminthic Treatment Delay the Progression of HIV? Randomised Open‐label Trial Testing Presumptive Anthelminthic Treatment on Progression of HIV in ART‐naïve HIV‐positive Patients in a Rural African Setting With Presumed High Prevalence of Helminth Infections	Standard HIV care with provision of praziquantel, albendazole, and ivermectin at baseline, after 6 months, and after 12 months versus standard HIV care with no anthelminthic treatment	• Change in viral load • Change in CD4 count • Adverse event	HIV‐infected individuals aged ≥ 18 years	Tanzania	Terminated prematurely due to recruitment difficulties
Abbreviations: RCT: randomized controlled trial; HIV: human immunodeficiency virus; ART: antiretroviral.

Table 14. Ongoing or planned RCTs

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Comparison 1. Deworming drugs versus placebo in people with unknown helminth infection status

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Viral load: change in log₁₀ HIV‐1 RNA Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1 At 6 weeks after one dose	1	166	Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.35, 0.07]
1.2 At 2 years after multiple doses	1	917	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.03, 0.05]
2 Change in CD4 count Show forest plot	1	917	Mean Difference (IV, Random, 95% CI)	2.60 [‐10.15, 15.35]

2.1 At 2 years after multiple doses	1	917	Mean Difference (IV, Random, 95% CI)	2.60 [‐10.15, 15.35]

Comparison 1. Deworming drugs versus placebo in people with unknown helminth infection status

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Comparison 2. Deworming drugs versus placebo in people with confirmed helminth infection

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Viral load: change in log₁₀ HIV‐1 RNA Show forest plot	4	445	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.26, ‐0.00]

1.1 Soil‐transmitted helminths	2	273	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.31, 0.12]
1.2 Schistosomiasis	2	161	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.36, 0.10]
1.3 Lymphatic filariasis	1	11	Mean Difference (IV, Random, 95% CI)	‐0.08 [‐0.93, 0.77]
2 Change in CD4 count Show forest plot	3	358	Mean Difference (IV, Random, 95% CI)	37.86 [7.36, 68.35]

2.1 Soil‐transmitted helminths	2	228	Mean Difference (IV, Random, 95% CI)	40.69 [1.51, 79.87]
2.2 Schistosomiasis	1	130	Mean Difference (IV, Random, 95% CI)	33.5 [‐15.06, 82.06]

Comparison 2. Deworming drugs versus placebo in people with confirmed helminth infection

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Comparison 3. Deworming drugs versus placebo; all trials

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in log₁₀ HIV RNA, by antihelminthic Show forest plot	5	1534	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.19, 0.01]

1.1 Albendazole	2	302	Mean Difference (IV, Random, 95% CI)	‐0.18 [‐0.37, 0.02]
1.2 Praziquantel	2	213	Mean Difference (IV, Random, 95% CI)	‐0.17 [‐0.32, ‐0.03]
1.3 Diethylcarbamazine	1	11	Mean Difference (IV, Random, 95% CI)	‐0.08 [‐0.93, 0.77]
1.4 Albendazole and praziquantel	2	1008	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.04, 0.05]
2 Difference in adverse events between treatment and no treatment groups Show forest plot	7	1649	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.53, 2.83]

3 Difference in mortality events between treatment and no treatment groups Show forest plot	5	1627	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.52, 1.14]

Comparison 3. Deworming drugs versus placebo; all trials

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