Supplementary Appendix Table of Contents

Transcription

1 Supplementary Appendix Table of Contents Appendix Figure 1. Scatter plots showing the number of clinical trials (Panel A) and total sample size (Panel B) and the global burden of disease measured in disability-adjusted life-years ab... 2 Appendix Figure 2. Network diagrams for disease entities with randomised controlled trials... 3 Appendix Table 1. Search terms for PubMed and Cochrane Central Register of Controlled Trials searches... 6 Appendix Table 2. Designation of first- and second-line therapies in Figure 2 network diagrams and Appendix Table 3 for the nine diseases with no WHO or consensus guidelines... 7 Appendix Table 3. Regimens compared, number of trials and number of subjects for each disease References

2 Total Sample Size Number of Clinical Trials Appendix Figure 1. Scatter plots showing the number of clinical trials (Panel A) and total sample size (Panel B) and the global burden of disease measured in disability-adjusted life-years ab Panel A Leishmaniasis 160 Geohelminths 140 Schistosomiasis 120 Leprosy Panel B Onchocerciasis Trachoma Dengue Rabies Chagas Echinococcus Foodborne trematodes HAT Lymphatic Filariasis Disability Adjusted Life-Years in Thousands Geohelminths Schistosomiasis Onchocerciasis Leishmaniasis Leprosy a See primary publication for sources for global burden of disease estimates b In this figure, the number of clinical trials and the total sample size was calculated from all 971 eligible randomised controlled trials (not just those addressing the primary disease). HAT=human African trypanosomiasis. Dengue Chagas Foodborne trematodes Echinococcosis Rabies HAT Trachoma 2 Lymphatic Filariasis Disability Adjusted Life-years in Thousands

3 Appendix Figure 2. Network diagrams for disease entities with randomised controlled trials Cysticercosis (32 trials) Albendazole+praziquantel Albendazole+corticosteroids Albendazole Praziquantel+corticosteroids Praziquantel Corticosteroids Placebo/No antiparasitics or steroids Trachoma individual treatment (29 trials) Topical spiramycin Topical rifampin Topical sulphafurazole+sdm Oral mino SMP Topical TCN Topical picloxydine SDM Oral erythromycin Topical sulfa drugs Placebo/NT Oral azithromycin Topical azithromycin Oral sulfisoxazole Trisulfapyrimidines Oral sulfafurazole Oral TCN Oral doxycycline Oral bactrim Topical TCN+polymixin B Topical TCN+oral erythromycin Herbal eyedrops 3

4 Paucibacillary leprosy (20 trials) Rifampin+levofloxacin+minocycline Sulforthomidine Thiambutosine Sulfamethoxine ROM ROM+clarithromycin Acetylazide Sulfamethoxypyridazine Dapsone Rifampin+dapsone Rifampin Clofazimine+dapsone+rifampin Dapsone+prednisolone Echinococcosis (15 trials) Rifampin+ofloxacin Percutaneous drainage Percutaneous drainage+albendazole Surgery+albendazole Albendazole Surgery Mebendazole Placebo/NT/watchful waiting Albendazole+praziquantel+surgery 4

5 Strongyloidiasis (14 trials) Thiabendazole Ivermectin Placebo/NT Albendazole Mebendazole Tribendimidine In the paucibacillary leprosy network, one trial which included regimens that are not compared with any of those shown in the connected network was omitted. Mino=minocycline. Placebo/NT=placebo or no treatment. ROM=rifampin, ofloxacin plus minocycline. SDM=sulfadimethoxine. SMP=sulfamethoxypyridazine. TCN=tetracycline. 5

6 Appendix Table 1. Search terms for PubMed and Cochrane Central Register of Controlled Trials searches Search Terms for PubMed Search Terms for Cochrane Central Register of Controlled Trials Leishmaniasis leishmaniasis[mesh] or leishman* or kalaazar leishmaniasis or kala-azar or leishman* Geohelminthiases ascariasis[mesh] or ascari*[tw] or strongyloidiasis[mesh] or strongyl*[tw] or ancylostomatoidea[mesh] or "hookworm" or Ancylostoma[tw] or Necator[tw] or ascar* or trichur* or strongyloid* or whipworm or ancylo* or hookworm or Necator or intestinal nematodes or soil-transmitted helminths trichuris[mesh] or trichur*[tw] or "whipworm" or "soil-transmitted helminths" or "geohelminths" Schistosomiasis schistosomiasis[mesh] or schistosomiasis or schistosom* or schistosomiasis or bilharz* bilharz* Leprosy leprosy[mesh] or leprosy leprosy or mycobacterium leprae or erythema nodosum leprosum Lymphatic filariasis Elephantiasis, filarial [MeSH] or lymphatic filariasis or Wuchereria bancrofti or Brugia lymphatic filariasis or Brugia* or Wuchereria or elephantiasis, filarial malayi or wucherer*[tw] or brugia*[tw] Onchocerciasis onchocerciasis[mesh] or onchocerciasis or onchocerc* or river blindness Onchocerciasis or onchocerc* or river blindness Trachoma trachoma[mesh] or trichiasis or trachoma trachoma or trichiasis Rabies rabies[mesh] or rabies Rabies Cysticercosis cysticercosis[mesh] or cysticercosis or neurocysticercosis or Taenia solium cysticercosis or neurocysticercosis or Taenia solium Dengue American trypanosomiasis Echinococcosis Foodborne trematodiases Human African trypanosomiasis Dracunculiasis Buruli ulcer dengue[mesh] or dengue or dengue hemorrhagic fever or dengue shock syndrome trypanosomiasis, American [MeSH] or Chaga* disease echinococcosis[mesh] or echinococc* or hydatid cyst or multilocularis or granulosus or hydatid* trematoda and foodborne [MeSH] or foodborne trematodes or clonorch* or opisthorch* or paragonim* or fasciolop* or fasciol* or intestinal flukes trypanosomiasis, African [MeSH] or human African trypanosomiasis dracunculus nematodes[mesh] or Guinea worm or dracontiasis or dracunculosis Buruli ulcer[mesh] or Buruli ulcer or Mycobacterium ulcerans Dengue or dengue hemorrhagic fever or dengue shock syndrome Chagas disease or American trypanosomiasis echinococc* or hydatid cyst or multilocularis or granulosus Opisthorchis or opisthorch* or clonorch* or clonorchis or paragon* or fasciol* or intestinal flukes or foodborne trematodes African trypanosomiasis or sleeping sickness Guinea worm or dracunculiasis Buruli ulcer or Mycobacterium ulcerans The PubMed search was done first and was intentionally broad and redundant. The medical subject heading (MeSH) term for each disease was used followed by additional search terms which we thought could capture additional trials. The randomised controlled trial limit was used for the PubMed searches. For the Cochrane Central Register of Controlled Trials search, we used the search terms shown in Appendix Table 1 in a text word search. 6

7 Appendix Table 2. Designation of first- and second-line therapies in Figure 2 network diagrams and Table S3 for the nine diseases with no WHO or consensus guidelines The Medical Letter UpToDate Final Arbitration Notes / References First-line First-line First-line Second-line Second-line Second-line Ascariasis Albendazole, mebendazole or ivermectin Albendazole or mebendazole Ivermectin, or nitazoxanide or piperazine citrate or levamisole Albendazole, mebendazole, pyrantel pamoate, levamisole Ivermectin, piperazine citrate, nitazoxanide Trichuriasis Mebendazole Mebendazole or Mebendazole or albendazole albendazole Albendazole or ivermectin Ivermectin Ivermectin Hookworm Albendazole or mebendazole or pyrantel pamoate Albendazole Mebendazole or pyrantel pamoate Strongyloidiasis Ivermectin Ivermectin Ivermectin Albendazole Albendazole Albendazole Onchocerciasis Ivermectin Ivermectin in endemic areas Ivermectin plus doxycycline in non-endemic or lowtransmission areas Mebendazole, albendazole, pyrantel pamoate, levamisole Ivermectin or doxycycline plus ivermectin Schistosomiasis Praziquantel Praziquantel Praziquantel Oxamniquine for S. Oxamniquine mansoni only Lymphatic filariasis (Wuchereria bancrofti, Brugia Diethylcarbamazine Diethylcarbamazine with or without albendazole in endemic areas without Diethylcarbamazine, or diethylcarbamazine plus albendazole First-line therapy was based on Bethony et al. 1 which concurred with agents recommended by WHO 2. All other drugs recommended in either The Medical Letter or UpToDate were designated second-line. First-line therapy was based on Bethony et al. 1 which concurred with the recommendations from UpToDate. First-line therapy was based on Bethony et al. 1 which concurred with agents recommended by WHO 2. Doxycycline plus ivermectin alone and doxycycline plus albendazole alone are recommended by other 7

8 malayi, Brugia timori only) Visceral leishmaniasis Cutaneous leishmaniasis Liposomal amphotericin, sodium stibogluconate or miltefosine Meglumine antimoniate or amphotericin B deoxycholate or paromomycin Sodium stibogluconate or meglumine antimoniate or miltefosine onchocerciasis or loiasis coinfection Doxycycline plus ivermectin or albendazole in nonendemic areas Liposomal amphotericin B Pentavalent antimonials a, miltefosine, or liposomal Amphotericin B deoxycholate or sodium stibogluconate or miltefosine Systemic sodium stibogluconate or meglumine antimoniate amphotericin Amphotericin B deoxycholate, paromomycin or lipid complex amphotericin Old World disease: Intralesional pentavalent antimonials a or systemic pentavalent antimonials a sources 3 but not represented in our dataset. Paromomycin or pentamidine Paromomycin or pentamidine New World disease: Systemic pentavalent antimonials a Old World disease: Heat therapy New World disease: Miltefosine or pentamidine Heat therapy was included as a second-line therapy for Old World disease and miltefosine for New World disease based on Reithinger et al. 4 Mucocutaneous leishmaniasis Sodium stibogluconate, or meglumine antimoniate or amphotericin B deoxycholate or miltefosine Sodium stibogluconate, or meglumine antimoniate or amphotericin B deoxycholate Pentavalent antimonials a or amphotericin B deoxycholate Chagas disease Nifurtimox or benznidazole Nifurtimox or benznidazole Nifurtimox or benznidazole Clonorchiasis Praziquantel or albendazole Praziquantel Praziquantel Albendazole is not represented in Albendazole our dataset 8

9 Opisthorchiasis Praziquantel Praziquantel Praziquantel Mebendazole is not represented Mebendazole in our dataset Fascioliasis Triclabendazole Triclabendazole Triclabendazole Bithionol is not represented in our Bithionol or nitazoxanide Bithionol or nitazoxanide Nitazoxanide dataset Fasciolopsiasis Praziquantel Praziquantel Praziquantel Paragonimiasis Praziquantel Praziquantel or triclabendazole Praziquantel or triclabendazole Bithionol is not represented in our dataset Bithionol African trypanosomiasis (late-stage Eflornithine or melarsoprol Eflornithine plus nifurtimox or eflornithine Eflornithine, eflornithine plus nifurtimox or melarsoprol Trypanosoma Melarsoprol brucei gambiense only) Dracunculiasis No curative treatment No treatment addressed No designation a Includes meglumine antimoniate and sodium stibogluconate. We reviewed the first- and second-line therapies listed in The Medical Letter 5 and UpToDate. In general, if either source listed a regimen as a first-line therapy we included it as a first line therapy. Where the two sources differed we used a review article, recent RCTs and own judgment to designate first- and second-line therapies. 9

10 Appendix Table 3. Regimens compared, number of trials and number of subjects for each disease Leishmaniasis New World cutaneous leishmaniasis New World mucocutaneous leishmaniasis Old World cutaneous leishmaniasis Visceral leishmaniasis Number of trials (Number of subjects a ) 184 (23039) 44 (3574) 7 (285) 61 (6338) 67 (12635) Treatment regimen b (number of trials number of subjects) Pentavalent antimonials ( ) Miltefosine (5 398); Pentamidine (2 55) Topical paromomycin/aminoglycoside (4 174); Sodium stibogluconate plus albendazole, ivermectin and praziquantel (1 45); Leishmaniasis vaccine plus pentavalent antimonials (2 78); Nitric oxide patch (1 88); Pentavalent antimonials plus imiquimod (3 67); Azithromycin (1 22); Imiquimod (1 6); Heat therapy (2 39); Pentavalent antimonials plus GM-CSF (2 20); Mefloquine (1 10); Topical aminoglycoside plus pentavalent antimonials (1 89); Allopurinol (3 108); Pentavalent antimonials plus interferon gamma (1 22); Pentavalent antimonials plus allopurinol (2 86); Aminosidine (3 122); Ketoconazole (2 62); BCG plus killed Leishmania (2 178); BCG (1 42); Placebo/no treatment (9 274) Pentavalent antimonials (6 157); Amphotericin B deoxycholate(1 10) Leishmaniasis vaccine plus pentavalent antimonials (1 36); Pentavalent antimonials plus allopurinol (1 40); Aminosidine (1 21); Pentavalent antimonials plus pentoxifylline (1 11); Amphotericin B deoxycholate plus itraconazole (1 10) Pentavalent antimonials (16 863) Heat therapy (3 224) Miltefosine (1 32); Cryotherapy (4 356); Cryotherapy plus intralesional pentavalent antimonials (3 215); Fluconazole (2 226); Intralesional pentavalent antimonials ( ); Intralesional 7% NaCl (3 119); Intralesional plus systemic pentavalent antimonials (2 30); Intralesional sodium stibogluconate plus ketoconazole (1 10); Intralesional ciprofloxacin (1 35); Topical paromomycin/aminoglycoside (12 752); Azithromycin (1 22); Systemic pentavalent antimonials plus topical honey (1 50); Pentavalent antimonials plus imiquimod (1 59); Rifampicin (3 96); Phototherapy (2 40); Pentavalent antimonials plus pentoxifylline (1 32); Intralesional zinc sulfate (3 104); Itraconazole (5 210); Topical azoles (2 103); Allopurinol (2 70); Allopurinol plus pentavalent antimonials (2 86); Ketoconazole (2 96); Oral zinc sulfate (1 115); Herbal extract (1 86); Topical eosin plus alcohol (1 57); Diminazene (1 35); Cetrimide and chlorhexidine (1 35); Intralesional interferon gamma (1 20); Dapsone (1 60); Topical interferon beta (1 7); Trichloroacetic acid (1 40); CO2 laser therapy (1 123); Placebo/no treatment (22 856) Liposomal amphotericin (7 758); Pentavalent antimonials ( ); Miltefosine (5 754) Amphotericin B ( ); Paromomycin (5 1098); Amphotericin B colloidal dispersion (1 405); Amphotericin B 10

11 Post-Kala-azar dermal leishmaniasis Amphotericin B deoxycholate-related nephropathy Old World visceral leishmaniasis secondary prophylaxis Geohelminths Strongyloidiasis Hookworm Trichuriasis 3 (160) 2 (68) 1 (17) 160 (46887) 14 (2970) 77 (27574) 66 (28079) lipid complex (5 284) Pentamidine (5 293); Pentavalent antimonials plus allopurinol (1 32); Pentavalent antimonials plus ketoconazole (1 32); Pentavalent antimonials plus levamisole (1 32); Sitamniquine (3 258); Liposomal amphotericin plus miltefosine (1 160); Liposomal amphotericin plus paromomycin (1 159); Miltefosine plus paromomycin (1 159); Paromomycin plus pentavalent antimonials (2 235); Artesunate plus sulfamethoxypyrazine pyrimethamine (1 20); Pentamidine plus allopurinol (1 80); Aminosidine (1 90); Pentavalent antimonials plus interferon gamma (3 130); Ketoconazole (1 90); Aminosidine plus pentavalent antimonials (2 237); Pentavalent antimonials plus pentamidine (1 208); Ethambutol (1 25); Ethambutol plus INH (1 5); Metronidazole (1 15); Trimethoprim-sulfamethoxazole (1 20); INH plus rifampin (1 10); Placebo/no treatment (1 21) Sodium stibogluconate (2 123); Amphotericin B deoxycholate (1 11); Sodium antimony gluconate (1 11); Leishmaniasis vaccine plus BCG plus sodium stibogluconate (1 15) Pre-amphotericin saline (2 33); Pre-amphotericin D5W (1 10); Oral rehydration solution (1 25) Amphotericin B lipid complex (1 8); Placebo/no treatment (1 9) Ivermectin (6 803) Albendazole ( ) Thiabendazole (3 38); Tribendimidine (1 81); Mebendazole (1 48); Placebo/no treatment (3 934) Albendazole ( ); Mebendazole ( ); Pyrantel pamoate ( ); Levamisole (3 400) Trichloroethylene (8 274); Bephenium (11 383); Bitoscanate (3 109); Phenylene diisothiocyanate plus trichloroethylene (1 12); Phenylene diisothiocyanate (2 63); Neobedermin (1 32); Pyrantel emboate (2 83); Tetramisole (4 302); Metrifonate (3 371); Praziquantel (2 453); Oxantel-pyrantel pamoate (2 541); DEC (2 339); Ivermectin (9 1438); Thiabendazole (4 90); Tribendimidine (1 81); Flubendazole (2 110); Piperazine plus bephenium (1 47); Fenbendazole (1 17); Mebendazole plus albendazole (1 83); Ivermectin plus albendazole (2 330); Albendazole plus DEC (1 310); Carica papaya seeds (1 30); Albendazole plus praziquantel (2 444); Levamisole plus mebendazole (1 286); Placebo/no treatment ( ) Mebendazole ( ) Albendazole ( ); Ivermectin (5 1432) Pyrantel pamoate (9 1175); Piperazine plus bephenium (1 47); Fenbendazole (1 17); Mebendazole plus 11

12 Ascariasis Anemia associated with geohelminths Nutritional deficiency associated with geohelminths Growth impairment associated with geohelminths Mass treatment and/or prevention strategy for 79 (29073) 14 (4722) 4 (2035) 5 (652) 4 (988) albendazole (1 83); Flubendazole (3 163); Ivermectin plus albendazole (5 683); DEC (3 469); Albendazole plus DEC (4 516); Levamisole (4 382); Levamisole plus mebendazole (1 286); Pyrantel oxantel or oxypyrantel or pyrantel oxantel pamoate(4 640); Albendazole plus praziquantel (3 514); Praziquantel (1 353); Carica papaya seeds (1 30); Mebendazole plus pyrantel-oxantel pamoate (1 186); Tribendimidine (1 81); Mebendazole plus ivermectin (1 154); Nitazoxanide (1 20); Pyrantel emboate (1 208); Albendazole plus health education (1 2); Placebo/no treatment ( ) Mebendazole ( ); Albendazole ( ); Pyrantel pamoate ( ); Levamisole ( ) Ivermectin (5 1432); Piperazine (5 223); Nitazoxanide (1 35) Bephenium (3 516); Thienpydin (1 40); Thienpydin plus mebendazole (1 42); Pyrantel pamoate plus mebendazole (1 43); Micronutrients (1 186); Paico (1 30); Health education (1 1); Mebendazole plus health education (1 1); Praziquantel (2 428); Metronidazole (1 40); Piperazine plus metronidazole (1 41); Oxantel-pyrantel pamoate or pyrantel oxantel (2 524); Piperazine plus bephenium (1 47); Fenbendazole (1 17); Mebendazole plus albendazole (1 83); Flubendazole (1 89); Ivermectin plus albendazole (3 477); DEC (4 495); Albendazole plus DEC (3 469); Levamisole plus mebendazole (1 286); Albendazole plus praziquantel (2 444); Carica papaya seeds (1 30); Tribendimidine (1 81); Phenyl diisothiocyanate (1 59); Bitoscanate (1 62); Mebendazole plus pyrantel oxantel pamoate (1 186); Thiabendazole (1 52); Albendazole plus health education (1 2); Tetramisole (2 150); Placebo/no treatment ( ) Trichlorethylene (2 87); Oral iron (8 901); Trichlorethylene plus iron (2 88); IM iron (1 15); IV iron (1 15); Blood transfusion (2 60); Mebendazole plus chloroquine (1 56); Iron plus albendazole (2 369); Albendazole plus praziquantel (1 178); Mebendazole (2 426); Albendazole plus iron plus folate (1 32); Albendazole (1 29); Iron plus folate (1 35); Mebendazole plus iron (2 606); Iron-fortified food plus mebendazole (1 85); Iron-fortified food (1 88); Iron, folate plus mebendazole (1 274); Iron, folate, mebendazole plus multivitamins (1 273); Iron plus vitamin C (1 37); Levamisole plus iron (1 17); Levamisole (1 8); Placebo/no treatment ( ) Albendazole, praziquantel plus iron (1 100); Albendazole plus praziquantel (1 98); Iron (1 84); Vitamin A (1 118); Mebendazole (1 123); Basic meal (1 43); Basic meal plus dietary fat plus levamisole (1 43); Basic meal plus beta carotene rich food (1 43); Basic meal plus beta carotene rich food plus levamisole (1 43); Beta carotene rich food plus levamisole (1 43); Beta carotene rich food plus dietary fat (1 43); Albendazole (1 610); Placebo/no treatment (3 644) Pyrantel pamoate (2 125); Albendazole (3 236); Iron plus albendazole (1 34); Iron (1 36); Vitamin A (2 86); Albendazole plus vitamin A (1 25); Placebo/no treatment (3 110) Piperazine (1 306); Levamisole (2 181); Micronutrients (1 186); Placebo/no treatment (2 315); Placebo/no treatment (1 4) 12

13 one or more geohelminths Schistosomiasis Chronic schistosomiasis Acute schistosomiasis Bladder cancer Bilharzial ureter Esophageal varices Liver fibrosis Portal hypertension Ascites Schistosomal nephropathy Anemia related to schistosomiasis 142 (35026) 114 (31977) 1 (205) 8 (722) 1 (56) 6 (383) 1 (60) 5 (327) 1 (37) 1 (26) 3 (1139) Praziquantel ( ); Oxamniquine ( ) Albendazole, ivermectin plus praziquantel (1 116); Artesunate plus sulfalene (1 106); Artesunate (4 394); Mefloquine (1 19); Mefloquine plus artesunate (1 18); Artesunate plus sulfadoxine-pyrimethamine (2 46); Praziquantel plus artesunate (2 142); Artesunate plus sulfamethoxypyrazine-pyrimethamine (2 426); Artemetherlumefantrine (1 3); Artesunate plus amodiaquine (1 12); Miracid (2 211); Micronutrients (1 61); Micronutrients plus praziquantel (1 65); Praziquantel plus albendazole (1 417); Albendazole (1 387); Praziquantel plus calcitriol (1 16); Metrifonate ( ); Oltipraz (8 1285); Niridazole ( ); Metrifonate plus niridazole (1 578); Hycanthone (6 629); Potassium antimony nitrate (1 19); Lucanthone (3 160); Metrifonate plus praziquantel (1 39); Tartar emetic (1 18); Lucanthone plus tartar emetic (1 21); Phenithionate (1 463); Oxamniquine plus praziquantel (2 94); Praziquantel plus levamisole (1 10); Levamisole (1 10); Calcitriol (1 14); Placebo/no treatment ( ) Praziquantel plus artemether (1 98); Praziquantel (1 107) Radiation (various schedules) (3 185); Epirubicin (1 34); Cystectomy (4 163); Cystectomy plus radiation (3 105); Cystectomy plus radation plus misonidazole (1 27); Radiation plus misonidazole (1 30); Hexamethylmelamine (2 46); Pentamethylmelamine (1 25); Teniposide (1 24); No treatment (1 83) Ureteral stent (1 28); No ureteral stent (1 28) Injection sclerotherapy (5 174); Injection sclerotherapy plus propranolol (1 20); Sclerotherapy with ethanolamine (1 40); Band ligation (2 39); Medical management (2 110) Praziquantel, anluohuaxian plus interferon gamma (1 30); Praziquantel plus conventional therapy (1 30) Esophagogastric devascularization and splenectomy (4 106); Distal splenorenal shunt (5 118); Distal splenorenal shunt plus splenic artery ligation (1 15); Proximal splenorenal shunt (3 88) Furosemide, spironolactone plus prednisone (1 18); Furosemide plus spironolactone (1 19) Praziquantel plus oxamniquine (1 8); Praziquantel, oxamniquine plus prednisolone (1 10); Praziquantel, oxamniquine plus cyclosporine (1 8) Praziquantel (2 386); Praziquantel plus iron (1 109); Praziquantel plus micronutrients (1 109); Praziquantel plus iron plus micronutrients (1 109); Albendazole, praziquantel plus iron (2 51); Albendazole plus praziquantel (2 51); Iron (1 44); Placebo/no treatment (2 280) 13

14 Hepatosplenomegaly associated with Schistosoma mansoni infection Leprosy Tuberculoid / paucibacillary (PB) leprosy 1 (94) Praziquantel (1 94) 120 (14772) 21 (5303) Rifampin and dapsone ( ) Rifampin plus ofloxacin plus minocycline (5 1060); Rifampin plus ofloxacin plus minocycline plus clarithromycin (1 149); Rifampin plus ofloxacin (2 98); Clofazimine plus dapsone plus rifampin (2 190); Rifampin plus clofazimine (1 317); Rifampin, clofazimine, dapsone, ethionamide (1 305); Rifampin (4 599); Dapsone (5 155); Rifampin, minocycline plus levofloxacin (1 36); Dapsone plus prednisone (1 70); Acetylazide (1 5); Thiambutosine (1 5); Sulfamethoxypyridazine (1 5); Sulforthomidine (1 5); Sulfamethoxine (1 5) Lepromatous / multibacillary (MB) leprosy Claw deformity Foot drop 56 (6388) 1 (50) 1 (24) Rifampin, dapsone plus clofazimine (16 846) Rifampin, sparfloxacin, clarithromycin plus minocycline (1 18); Ethionamide (1 25); Prothionamide (2 45); Rifampin, dapsone plus clofazimine plus vitamin E (1 25); Rifampin, dapsone, clofazimine plus BCG (2 40); Rifampin, dapsone, clofazimine plus M. w. vaccine (3 178); Rifampin, dapsone, clofazimine plus pefloxacin (2 22); Rifampin, dapsone, clofazimine plus ofloxacin (3 41); Rifampin, dapsone, clofazimine plus interferon gamma (1 10); Rifampin, dapsone, clofazimine plus interferon-alpha (1 20); Rifampin (6 115); Dapsone plus clofazimine (4 176); Clarithromycin plus minocycline ( 2 22); Clarithromycin, minocycline plus ofloxacin (1 10); Rifampin, dapsone, clofazimine plus M. leprae vaccine plus BCG (1 30); Isoniazid, prothionamide plus dapsone (1 75); Rifampin plus multivitamin (1 29); Clofazimine, dapsone plus ofloxacin (3 46); Ofloxacin (1 16); Rifampin, ethionamide plus dapsone (1 268); Dapsone plus diphenylurea (1 53); Dapsone plus diphenylurea plus Etisul (1 33); Sulfone (1 40); Sulfone plus INH (1 40); INH, dihydrostreptomycin plus PAS (1 39); Dapsone plus Etisul (1 124); Dapsone plus BCG (1 44); Dapsone plus nicotinamide (1 172); Dapsone, nicotinamide and BCG (1 47); Pyrazinamide plus INH (1 30); Rifampin, ofloxacin plus minocycline then rifampin, dapsone plus clofazimine (1 10); Ofloxacin plus minocycline then rifampin, dapsone plus clofazimine (1 10); Dapsone plus thiacetazone (1 206); Dapsone, thiacetazone plus rifampin (1 191); Minocycline (1 12); Clarithromycin (1 12); Clofazimine (6 437); Clofazimine, dapsone plus pheniramine (1 52); Rifampin, prothionamide plus thiacetazone (1 29); Clofazimine plus rifampin (1 127); Rifampin, INH, clofazimine plus dapsone (1 104); INH, prothionamide; dapsone plus rifampin (2 366); Acedapsone (2 35); Acacia (1 10); Acacia plus dapsone (1 10); Dapsone plus antigen marianum (1 61); Dapsone, prothionamide plus rifampin (3 437); Dapsone plus rifampin (9 730); Dapsone (19 845); Acetylazide (1 5); Thiambutosine (1 5); Sulfamethoxypyridazine (1 5); Sulforthodimethoxine (1 5); Sulfadimethoxine (1 5) Early mobilization after surgery (1 25); Immobilization after surgery (1 25) Early mobilization after surgery (1 13); Immobilization after surgery (1 11) 14

15 Leprosy ulcers Peripheral blood flow chronic leprosy Osteoporosis Leprous neuritis / neuritis in lepra reaction / treatment of nerve impairment / ulnar neuritis 10 (517) 1 (103) 1 (23) 7 (394) Laser therapy (1 13); Topical phenytoin (1 30); Topical ketanserin (1 33); Topical clioquinol (1 33); Pulsed magnetic field and standard therapy (1 20); Zinc oxide tape and povidone iodine (1 26); Povidone iodine (1 12); Zinc oxide tape (2 64); Conventional below the knee plaster of Paris (1 24); Moulded double plaster of Paris shoe (1 31); Hydergine (1 10); Topical and injectable extract of Centella asiatica (1 33); Topical extract of Centella asiatica (1 33); Standard therapy (various) or placebo (7 155) M. vaccae (1 52); Placebo/no treatment (1 51) Risedronate (1 12); Placebo/no treatment (1 11) Steroids (4 147); Steroids plus surgery (2 82); Isaxonine (1 15); Ambulatory care (1 13); Inpatient care (1 13); Surgical management (1 29); Medical management (1 28); Placebo/no treatment (2 67) Paucibacillary lepra reaction Multibacillary lepra reaction Erythema nodosum leprosum / Type 1 reaction / lepra reaction / lepromatous leprosy reaction 1 (335) 1 (257) 20 (1378) Rifampin and dapsone (1 184); Rifampin (1 151) Rifampin, ethionamide plus dapsone or clofazimine (1 257) Aspirin (2 56); Dapsone (3 241); Indomethacin (2 37); Chloroquine (1 12); Clofazamine plus dapsone (1 36); Thalidomide plus dapsone (1 36); Dapsone plus corticosteroids (1 98); Dapsone plus methandrostenolone (1 99); Dapsone plus mefenamic acid (1 103); Thalidomide (7 136); Pentoxifylline (1 24); Clofazimine (2 19); Levamisole plus dapsone (1 7); Corticosteroids (7 449); Placebo/no treatment (9 135); Filariasis 73 (9996) Albendazole plus ivermectin (8 623); DEC plus albendazole ( ); DEC ( ) DEC plus doxycycline (1 25); Albendazole (8 744); Doxycycline (5 278); Doxycycline plus albendazole plus ivermectin (2 36); Ivermectin ( ); DEC plus ivermectin (10 170); Centperazine (1 76); Levamisole plus DEC (1 19); Ayurvedic remedy (1 44); Albendazole plus ivermectin plus praziquantel (1 134); Coumarin (3 158); Coumarin plus DEC (2 87); Levamisole (1 56); Placebo/no treatment ( ) Onchocerciasis Onchocerca volvulus individual treatment 62 (25182) 53 (10940) Doxycycline plus ivermectin (2 150); Ivermectin ( ) Doxycycline (3 164); Rifampin plus ivermectin (1 21); Azithromycin plus ivermectin (1 21); Azithromycin plus rifampin plus ivermectin (1 20); Levamisole (4 51); Levamisole plus ivermectin (1 22); Levamisole plus albendazole (1 22); Albendazole (5 166); Ivermectin plus albendazole (3 63); DEC containing salt (1 20); 15

16 O. volvulus mass control strategy O. volvulus mass treatment and prevention Diethylcarbamazine (DEC) reaction Trachoma Active trachoma Trachoma mass control strategy Trachomatous dry eye Trichiasis 1 (1625) 4 (12489) 4 (128) 54 (10420) 29 (5316) 15 (1456) 1 (64) 9 (3584) Ivermectin plus amocarzine (1 34); Amocarzine (3 65); Levamisole plus mebendazole (5 65); DEC plus oral steroids (1 11); Topical DEC plus oral steroids (1 11); DEC (13 273); Flubendazole (1 10); Mebendazole (2 22); Levamisole plus flubendazole (1 20); Topical DEC (3 112); Metrifonate (4 80); Suramin (1 50); Suramin plus DEC (1 50); Placebo/no treatment ( ) Ivermectin (1 812); Placebo/no treatment (1 813) Ivermectin (4 7936); Placebo/no treatment (4 4553) DEC plus prednisone plus cyprohepatidine (1 20); DEC (4 63); DEC plus prednisone (1 23); DEC plus indomethacin (1 12); DEC plus cyprohepatidine (1 10) Oral azithromycin (8 871); Ophthalmic tetracyclines ( ) Ophthalmic azithromycin (2 449); Ophthalmic tetracycline plus topical polymixin B (3 116); Herbal eyedrops (1 19); Ophthalmic tetracycline plus oral erythromycin (1 97); Picloxydine (1 91); Topical sulfa drugs (2 144); Oral minocycline (2 79); Oral erythromycin (1 79); Ophthalmic rifampicin (2 89); Trimethoprim-sulfamethoxazole (1 25); Oral doxycycline (2 96); Oral tetracycline (2 53); Oral sulphafurazole (1 34); Oral sulfamethoxypyridazine (1 112); Ophthalmic spiramycin (1 41); Ophthalmic sulfphafurozole plus oral sulfphamethoxine (1 78); Oral sulfphadimethoxine (2 83); Oral trisulfapyrimidines (1 18); Oral Sulfisoxazole (1 34); Placebo/no treatment (16 859) Oral azithromycin (7 83); Ophthalmic tetracycline (5 179) Oral azithromycin plus permethrin insecticide spraying (1 8); Targeted treatment with oral azithromycin (1 6); Mass treatment with ophthalmic tetracycline plus face washing (1 3); Mass treatment with ophthalmic tetracycline plus education (1 1); Education (1 1); Oral doxycycline (1 166); Vaccine (1 132); Antibiotics (various) (2 264); Vaccine plus antibiotics (various) (2 262); Surgery for trichiasis plus antibiotics (various) plus facial cleanliness plus environmental improvements (1 1); Surgery for trichiasis plus antibiotics (various) (1 1); Surgery for trichiasis (1 1); Sulphametopyrazine (1 112); Oral azithromycin plus NGO activities plus radio messages plus educational materials (1 10); Radio messages plus NGO activities plus oral azithromycin (1 10); Radio messages plus NGO activities plus oral azithromycin plus educational materials plus video education (1 10); Placebo/no treatment (6 206) Cyclosporine eye drops (1 32); Placebo/no treatment (1 32) Azithromycin to index patient (1 483); Azithromycin to index patient and household contacts (2 701); Ophthalmic 16

17 Rabies Rabies true postexposure treatment Rabies simulated exposure or low risk exposure 45 (6756) 13 (2129) 32 (4627) tetracycline (2 719); Tarsal rotation (2 180); Tarsal rotation plus tarsoconjunctival advancement (1 30); Anterior lamellar repositioning (1 30); Surgery by ophthalmologist (1 370); Surgery by integrated eyecare worker (1 343); Bilamellar tarsal rotation (2 165); Tarsotomy (1 132); Village-based surgery (1 8); Health centre based surgery (1 8); Sticking plaster (1 21); Sticking plaster plus epilation (1 18); Epilation (1 18); Electrolysis (1 57); Cryoablation (1 57); Tarsal advancement and rotation (2 133); Tarsal advancement and grafting (1 11); Eversion splinting (1 24); Tarsal advancement (1 41); Tarsal grooving (1 35) Purified Vero cell vaccine IM (3 399); Purified chick embryo cell vaccine ID (4 171); Purified chick embryo cell vaccine IM (4 134); Chromatographically purified Vero cell vaccine IM (1 200); Purified duck embryo vaccine IM (1 52); Human diploid cell rabies vaccine IM (1 10); Chromatographically purified Vero cell vaccine IM plus rabies immunoglobulin (2 255); Purified chick embryo cell vaccine IM plus rabies immunoglobulin (2 159); Purified Vero cell vaccine ID (2 374); Human diploid cell rabies vaccine ID plus immunoglobulin (1 78); Human diploid cell vaccine IM plus immunoglobulin (1 39); Purified Vero cell vaccine IM plus immunoglobulin IM (1 47) Fetal bovine kidney cell vaccine IM or SC plus immunoglobulin (1 40); Human diploid cell rabies vaccine IM plus vitamin C (1 6); Rabies vaccine IM plus vitamin A (1 20); Rabies vaccine IM (1 20); Brain tissue vaccine (2 125) Chromatographically purified Vero cell vaccine IM (2 506); Purified Vero cell vaccine ID (4 389); Purified Vero cell vaccine IM (6 503); Purified duck embryo vaccine IM (2 236); Purified chick embryo cell vaccine ID (9 1297); Chromatographically purified Vero cell vaccine IM plus human rabies immunoglobulin IM (1 124); Human diploid cell rabies vaccine IM plus human rabies immunoglobulin IM (5 185); Purified chick embryo cell vaccine IM (6 220); Purified chick embryo cell vaccine ID plus human rabies immunoglobulin (2 83); Human diploid cell vaccine IM (5 223); Purified chick cell embryo vaccine IM plus human rabies immunoglobulin (3 55); Purified duck embryo vaccine IM plus human rabies immunoglobulin (2 24); Purified Vero cell vaccine IM plus human rabies immunoglobulin IM (2 19); Human diploid cell rabies vaccine ID (3 92); Monoclonal rabies antibody IM (1 59); Monoclonal rabies antibody IM and purified chick embryo cell vaccine (1 23) ; Purified heat treated equine rabies immunoglobulin (1 14); Standard commercial equine rabies immunoglobulin (1 15); Purified Vero cell vaccine IM plus purified heat treated equine rabies immunoglobulin (1 36); Purified Vero cell vaccine IM plus standard commercial equine rabies immunoglobulin (1 36); Human rabies immunoglobulin (1 16); Heat treated human rabies immunoglobulin (1 16); Heat treated human rabies immunoglobulin plus human diploid cell rabies vaccine IM (2 42); Purified Vero cell vaccine IM plus tetanus toxoid (1 15); Purified Vero cell vaccine IM plus aluminum-free tetanus toxoid (1 15); Fetal bovine kidney cell vaccine IM (2 64); Fetal bovine kidney cell vaccine IM plus human rabies immunoglobulin (1 10); Human diploid cell vaccine ID or IM (not specified) (1 90); Human diploid cell rabies vaccine SC (3 31); Human diploid cell rabies vaccine SC plus human rabies immunoglobulin IM (2 13); Human diploid cell rabies vaccine SC plus human rabies immunoglobulin IV (1 6); Human rabies immunoglobulin IV (1 6); Semple vaccine SC (1 17); Human diploid cell rabies vaccine plus adjuvant IM (1 16); Human diploid cell rabies vaccine plus adjuvant SC (1 20); Human diploid cell rabies vaccine plus adjuvant ID plus human rabies immunoglobulin IM (1 19); Human diploid cell rabies vaccine plus adjuvant SC plus human rabies immunoglobulin (1 12); Suckling mouse brain vaccine SC (1 16); 17

18 Suckling mouse brain vaccine SC plus human rabies immunoglobulin (1 16); Purified chick cell embryo vaccine ID plus equine rabies immunoglobulin (1 15); Purified chick cell embryo vaccine IM plus equine rabies immunoglobulin (1 15); Placebo/no treatment (1 18) Cysticercosis 32 (2872) Albendazole plus corticosteroids (12 690); Praziquantel plus corticosteroids (2 64) Praziquantel (3 93); Corticosteroids (9 369); Albendazole plus praziquantel (1 58); Albendazole (15 646); Placebo/no treatment (no antiparasitics or corticosteroids) (16 952) Dengue Dengue hemorrhagic fever (DHF) resuscitation fluid Dengue shock syndrome (DSS) resuscitation fluid Dengue fever (DF) Thrombocytopenia associated with DF DF and DHF Bleeding associated with DHF DSS corticosteroids Respiratory failure associated with DSS American Trypanosomiasis Chronic Chagas disease 24 (2374) 2 (141) 6 (890) 3 (387) 4 (377) 1 (114) 1 (25) 6 (403) 1 (37) 22 (1772) 8 (1273) Dextran 40 (1 57); Haes-Steril (1 47); AC-17 plus lactated Ringer s (1 18); Normal saline plus lactated Ringer s (1 19) Lactated Ringer s (3 196); 6% Dextran 70 (4 260); 6% hydroxylethyl starch (2 191); Normal saline (3 73); Haemaccel (1 6); Gelafundin (2 69); AC-17 (1 45); Placebo/no treatment (1 50) Chloroquine (1 153); Homeopathic remedy (1 29); Calcium carbonate (1 10); Placebo/no treatment (3 195) Dexamethasone (1 100); Fresh frozen plasma (1 53); Intravenous immunoglobulin (1 15); WinRho (1 25); Placebo/no treatment (4 184) Doxycycline (1 45); Tetracycline (1 35); Placebo/no treatment (1 34) Recombinant Factor VIIa (1 16); Placebo/no treatment (1 9) Methylprednisone (2 43); Hydrocortisone (4 149); Placebo/no treatment (6 211) Oxygen mask (1 19); Nasal CPAP (1 18) Benznidazole (5 429); Nifurtimox (1 27) Itraconazole (2 221); Allopurinol (3 213); Placebo/no treatment (7 383) Chagas cardiomyopathy Arrhythmias associated with cardiomyopathy Cardioneuropathy 4 (129) 3 (114) 1 (58) ACE inhibitor (2 26); Exercise program (1 21); Carvedilol (1 19); Placebo/no treatment (4 63) Carbamazepine (1 8); Flecainide (1 40); Amiodarone (1 41); Disopyramide (1 8); Disopyramide plus amiodarone (1 9); Placebo/no treatment (1 8) Cronassial (ganglioside therapy) (1 39); Placebo/no treatment (1 19) 18

19 Esophageal dysmotility 5 (87) Isosorbide dinitrate (3 30); Nifedipine (1 5); Botulinum toxin (2 15); Placebo/no treatment (4 37) Congenital infection 1 (111) Benznidazole (1 111) Echinococcosis 15 (1064) Surgery alone (8 279); Surgery plus albendazole (5 209); Albendazole (4 224); Percutaneous drainage plus albendazole (2 37); Placebo/no treatment/watchful waiting (2 64) Mebendazole (3 204) Albendazole plus praziquantel plus surgery (1 37); Percutaneous drainage (1 10) Foodborne trematodes 14 (1,306) a Fascioliasis 5 (549) Triclabendazole (4 399) Nitazoxanide (1 80) Artesunate (1 50); Placebo/no treatment (1 20) Clonorchiasis Opisthorchiasis Paragonimiasis 3 (181) 4 (316) 2 (216) Praziquantel (3 63); Amoscanate (1 26); Hexachloroparaxylol (1 29); Hexachloroparaxylol plus amoscanate (1 22); Placebo/no treatment (2 41) Praziquantel (3 140) Albendazole (1 55); Mefloquine (1 25); Artesunate (1 24); Mefloquine plus artesunate (1 24); Tribendimidine (1 27); Placebo/no treatment (1 21) Praziquantel (1 15); Triclabendazole (2 201) Fasciolopsiasis 1 (85) Praziquantel (1 85) Early and late stage African 10 (2,840) Melarsoprol (5 1865); Nifurtimox plus eflornithine (3 211); Eflornithine (4 536); Pentamidine (1 52) Trypanosomiasis Melarsoprol plus nifurtimox (2 87); Melarsoprol plus eflornithine (1 19); Nifurtimox (1 70) (Trypanosoma brucei gambiense) Dracunculiasis (Guinea 9 (798) Ivermectin (1 26); Mebendazole (1 33); Metronidazole (5 236); Niridazole (3 111); Thiabendazole (1 63) worm) Placebo/no treatment (9 329) Buruli ulcer 5 (337) Streptomycin plus rifampin (1 76); Streptomycin plus rifampin plus clarithromycin (1 75); Streptomycin plus rifampin followed by excision (1 16) Excision and closure (1 5); Topical sodium nitrate plus topical citric acid monohydrate (1 16); Dapsone plus rifampin (1 15); Clofazimine (1 51); Placebo/no treatment (3 83) a number of patients in each section do not add up to total as some trials addressed more than one disease b Solid underlined regimens are recommended 1 st line therapies, dotted underlined regimens are recommended 2 nd line therapies. ACE=angiotensin converting enzyme. BCG=Bacille Calmette-Guérin vaccine. CPAP=continuous positive airway pressure. DEC=diethylcarbamazine. GM-CSF=granulocyte macrophage colony-stimulating factor. ID=intradermal. IM=intramuscular. INH=isoniazid. NGO=non-governmental organization. PAS=p-aminosalicylic acid. SC=subcutaneous. 19

20 References 1. Bethony J, Brooker S, Albonico M, et al. Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet 2006;367: World Health Organization. Useful information on Schistosomiasis and STH. In: Programmes and Projects. Geneva, Switzerland: World Health Organization,. 3. Hoerauf A. Filariasis: new drugs and new opportunities for lymphatic filariasis and onchocerciasis. Curr Opin Infect Dis 2008;21: Reithinger R, Dujardin JC, Louzir H, Pirmez C, Alexander B, Brooker S. Cutaneous leishmaniasis. Lancet Infect Dis 2007;7: Anonymous. Drugs for Parasitic Infections. Treatment guidelines from The Medical Letter 2007;5 (Suppl):e1-e15. 20