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-yearsab ...... 2 Appendix Figure 2. Network diagrams for disease entities with 11-40 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 ...... 10 References ...... 20

1 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-yearsab

Panel A 200

Leishmaniasis 180

160 Geohelminths

140 Schistosomiasis

120 Leprosy

100

80 Lymphatic Filariasis Number of Clinical Trials 60 Onchocerciasis Trachoma Dengue Rabies 40 Chagas Echinococcus 20 Foodborne trematodes HAT 0 0 1000 2000 3000 4000 5000 6000 7000 Disability Adjusted Life-Years in Thousands Panel B

50000 Geohelminths 45000

40000

Schistosomiasis 35000

30000

25000 Onchocerciasis

Leishmaniasis Total Sample Size Total 20000

Leprosy 15000 Dengue Chagas Lymphatic Filariasis 10000 Foodborne trematodes Trachoma Echinococcosis Rabies 5000 HAT 0 0 1000 2000 3000 4000 5000 6000 7000 Disability Adjusted Life-years in Thousands aSee primary publication for sources for global burden of disease estimates bIn 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. 2 Appendix Figure 2. Network diagrams for disease entities with 11-40 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

Oral mino SMP Topical sulphafurazole+SDM Topical TCN

Oral erythromycin Topical picloxydine SDM

Topical sulfa drugs

Placebo/NT Oral azithromycin Topical azithromycin Trisulfapyrimidines Oral sulfafurazole Oral sulfisoxazole

Topical TCN+oral erythromycin Oral bactrim Oral TCN Topical TCN+polymixin B Oral doxycycline

Herbal eyedrops

3 Paucibacillary leprosy (20 trials)

Rifampin+levofloxacin+minocycline

Sulforthomidine

ROM Thiambutosine Sulfamethoxine ROM+clarithromycin

Rifampin+dapsone Acetylazide Dapsone Sulfamethoxypyridazine

Rifampin Clofazimine+dapsone+rifampin

Dapsone+prednisolone Rifampin+ofloxacin

Echinococcosis (15 trials)

Percutaneous drainage

Percutaneous drainage+albendazole Surgery+albendazole

Albendazole

Surgery

Mebendazole

Placebo/NT/watchful waiting

Albendazole+praziquantel+surgery

4 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 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 kala- leishmaniasis or kala-azar or leishman* azar Geohelminthiases ascariasis[MeSH] or ascari*[tw] or ascar* or trichur* or strongyloid* or whipworm strongyloidiasis[MeSH] or strongyl*[tw] or or ancylo* or hookworm or Necator or ancylostomatoidea[MeSH] or "hookworm" intestinal nematodes or soil-transmitted or Ancylostoma[tw] or Necator[tw] or 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 “Elephantiasis, filarial”[MeSH] or lymphatic lymphatic filariasis or Brugia* or Wuchereria or filariasis filariasis or Wuchereria bancrofti or Brugia elephantiasis, filarial malayi or wucherer*[tw] or brugia*[tw] Onchocerciasis onchocerciasis[MeSH] or onchocerciasis or Onchocerciasis or onchocerc* or river onchocerc* or “river blindness” blindness Trachoma trachoma[MeSH] or trichiasis or trachoma trachoma or trichiasis Rabies rabies[MeSH] or rabies Rabies Cysticercosis cysticercosis[MeSH] or cysticercosis or cysticercosis or neurocysticercosis or Taenia neurocysticercosis or “Taenia solium” solium Dengue dengue[MeSH] or dengue or “dengue Dengue or dengue hemorrhagic fever or hemorrhagic fever” or “dengue shock dengue shock syndrome syndrome” American “trypanosomiasis, American”[MeSH] or Chagas disease or “American trypanosomiasis” trypanosomiasis Chaga* disease Echinococcosis echinococcosis[MeSH] or echinococc* or echinococc* or hydatid cyst or multilocularis or “hydatid cyst” or multilocularis or granulosus granulosus or hydatid* Foodborne “trematoda and foodborne”[MeSH] or Opisthorchis or opisthorch* or clonorch* or trematodiases “foodborne trematodes” or clonorch* or clonorchis or paragon* or fasciol* or intestinal opisthorch* or paragonim* or fasciolop* or flukes or “foodborne trematodes” fasciol* or intestinal flukes Human African “trypanosomiasis, African”[MeSH] or human “African trypanosomiasis” or “sleeping trypanosomiasis African trypanosomiasis sickness” Dracunculiasis dracunculus nematodes[MeSH] or Guinea Guinea worm or dracunculiasis worm or dracontiasis or dracunculosis Buruli ulcer Buruli ulcer[MeSH] or Buruli ulcer or Buruli ulcer or Mycobacterium ulcerans 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 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 Albendazole or Albendazole, mebendazole, First-line therapy was based on or ivermectin mebendazole pyrantel pamoate, Bethony et al.1 which concurred levamisole with agents recommended by Ivermectin, or nitazoxanide Ivermectin, piperazine WHO2. All other drugs or piperazine citrate or citrate, nitazoxanide recommended in either The levamisole Medical Letter or UpToDate® were designated second-line. Trichuriasis Mebendazole Mebendazole or Mebendazole or First-line therapy was based on albendazole albendazole Bethony et al.1 which concurred Albendazole or ivermectin Ivermectin Ivermectin with the recommendations from UpToDate®. Hookworm Albendazole or Albendazole Mebendazole, albendazole, First-line therapy was based on mebendazole or pyrantel pyrantel pamoate, Bethony et al.1 which concurred pamoate levamisole with agents recommended by Mebendazole or pyrantel WHO2. pamoate Strongyloidiasis Ivermectin Ivermectin Ivermectin Albendazole Albendazole Albendazole Onchocerciasis Ivermectin Ivermectin in endemic Ivermectin or doxycycline areas plus ivermectin Ivermectin plus doxycycline in non-endemic or low- transmission areas Schistosomiasis Praziquantel Praziquantel Praziquantel Oxamniquine for S. Oxamniquine mansoni only Lymphatic filariasis Diethylcarbamazine Diethylcarbamazine with or Diethylcarbamazine, or Doxycycline plus ivermectin alone (Wuchereria without albendazole in diethylcarbamazine plus and doxycycline plus albendazole bancrofti, Brugia endemic areas without albendazole alone are recommended by other

7 malayi, Brugia onchocerciasis or loiasis co- sources3 but not represented in timori only) infection our dataset. Doxycycline plus ivermectin or albendazole in non- endemic areas Visceral Liposomal amphotericin, Liposomal amphotericin B Pentavalent antimonialsa, leishmaniasis sodium stibogluconate or miltefosine, or liposomal miltefosine amphotericin Meglumine antimoniate or Amphotericin B Amphotericin B amphotericin B deoxycholate or sodium deoxycholate, deoxycholate or stibogluconate or paromomycin or lipid paromomycin miltefosine complex amphotericin Cutaneous Sodium stibogluconate or Systemic sodium Old World disease: leishmaniasis meglumine antimoniate or stibogluconate or Intralesional pentavalent miltefosine meglumine antimoniate antimonialsa or systemic pentavalent antimonialsa

New World disease: Systemic pentavalent antimonials a Paromomycin or Paromomycin or Old World disease: pentamidine pentamidine Heat therapy Heat therapy was included as a second-line therapy for Old World New World disease: disease and miltefosine for New Miltefosine or pentamidine World disease based on Reithinger et al.4

Mucocutaneous Sodium stibogluconate, or Sodium stibogluconate, or Pentavalent antimonialsa or leishmaniasis meglumine antimoniate or meglumine antimoniate or amphotericin B amphotericin B amphotericin B deoxycholate deoxycholate or miltefosine 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 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 Praziquantel or Bithionol is not represented in our triclabendazole triclabendazole dataset Bithionol African Eflornithine or melarsoprol Eflornithine plus nifurtimox Eflornithine, eflornithine trypanosomiasis or eflornithine plus nifurtimox or (late-stage melarsoprol Trypanosoma Melarsoprol brucei gambiense only) Dracunculiasis No curative treatment No treatment addressed No designation aIncludes meglumine antimoniate and sodium stibogluconate.

We reviewed the first- and second-line therapies listed in The Medical Letter5 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 Appendix Table 3. Regimens compared, number of trials and number of subjects for each disease

Number of Treatment regimenb (number of trials | number of subjects) trials (Number of subjectsa) Leishmaniasis 184 (23039) New World cutaneous 44 (3574) Pentavalent antimonials (39 | 1589) leishmaniasis 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)

New World 7 (285) Pentavalent antimonials (6 | 157); Amphotericin B deoxycholate(1 | 10) mucocutaneous Leishmaniasis vaccine plus pentavalent antimonials (1 | 36); Pentavalent antimonials plus allopurinol (1 | 40); leishmaniasis Aminosidine (1 | 21); Pentavalent antimonials plus pentoxifylline (1 | 11); Amphotericin B deoxycholate plus itraconazole (1 | 10)

61 (6338) Pentavalent antimonials (16 | 863) Old World cutaneous Heat therapy (3 | 224) leishmaniasis Miltefosine (1 | 32); Cryotherapy (4 | 356); Cryotherapy plus intralesional pentavalent antimonials (3 | 215); Fluconazole (2 | 226); Intralesional pentavalent antimonials (19 | 1074); 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)

67 (12635) Liposomal amphotericin (7 | 758); Pentavalent antimonials (28 | 3026); Miltefosine (5 | 754) Visceral leishmaniasis Amphotericin B (23 |3999); Paromomycin (5 | 1098); Amphotericin B colloidal dispersion (1 | 405); Amphotericin B

10 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)

3 (160) Sodium stibogluconate (2 | 123); Amphotericin B deoxycholate (1 | 11); Sodium antimony gluconate (1 | 11); Post-Kala-azar dermal Leishmaniasis vaccine plus BCG plus sodium stibogluconate (1 | 15) leishmaniasis 2 (68) Pre-amphotericin saline (2 | 33); Pre-amphotericin D5W (1 | 10); Oral rehydration solution (1 | 25) Amphotericin B deoxycholate-related nephropathy 1 (17) Amphotericin B lipid complex (1 | 8); Placebo/no treatment (1 | 9) Old World visceral leishmaniasis secondary prophylaxis Geohelminths 160 (46887) Strongyloidiasis 14 (2970) Ivermectin (6 | 803) Albendazole (11 | 1066) Thiabendazole (3 | 38); Tribendimidine (1 | 81); Mebendazole (1 | 48); Placebo/no treatment (3 | 934)

Hookworm 77 (27574) Albendazole (40 | 7106); Mebendazole (27 | 5790); Pyrantel pamoate (16 | 1429); 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 (40 | 6560)

Trichuriasis 66 (28079) Mebendazole (25 | 6321) Albendazole (41 | 8739); Ivermectin (5 | 1432) Pyrantel pamoate (9 | 1175); Piperazine plus bephenium (1 | 47); Fenbendazole (1 | 17); Mebendazole plus

11 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 (34 | 5578)

Ascariasis 79 (29073) Mebendazole (24 | 5865); Albendazole (33 | 7526); Pyrantel pamoate (16 | 1878); Levamisole (12 | 1254) 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 (41 | 5939)

Anemia associated with 14 (4722) Trichlorethylene (2 | 87); Oral iron (8 | 901); Trichlorethylene plus iron (2 | 88); IM iron (1 | 15); IV iron (1 | 15); Blood geohelminths 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 (10 | 1043)

Nutritional deficiency 4 (2035) Albendazole, praziquantel plus iron (1 | 100); Albendazole plus praziquantel (1 | 98); Iron (1 | 84); Vitamin A (1 | 118); associated with Mebendazole (1 | 123); Basic meal (1 | 43); Basic meal plus dietary fat plus levamisole (1 | 43); Basic meal plus beta geohelminths 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)

Growth impairment 5 (652) Pyrantel pamoate (2 | 125); Albendazole (3 | 236); Iron plus albendazole (1 | 34); Iron (1 | 36); Vitamin A (2 | 86); associated with Albendazole plus vitamin A (1 | 25); Placebo/no treatment (3 | 110) geohelminths

Mass treatment and/or 4 (988) Piperazine (1 | 306); Levamisole (2 | 181); Micronutrients (1 | 186); Placebo/no treatment (2 | 315); Placebo/no prevention strategy for treatment (1 | 4)

12 one or more geohelminths Schistosomiasis 142 (35026) Chronic schistosomiasis 114 (31977) Praziquantel (76 | 14488); Oxamniquine (23 | 2419) 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); Artemether- lumefantrine (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 (16 | 4606); Oltipraz (8 | 1285); Niridazole (11 | 1212); 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 (38 | 3473)

Acute schistosomiasis 1 (205) Praziquantel plus artemether (1 | 98); Praziquantel (1 | 107)

Bladder cancer 8 (722) 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)

Bilharzial ureter 1 (56) Ureteral stent (1 | 28); No ureteral stent (1 | 28)

Esophageal varices 6 (383) Injection sclerotherapy (5 | 174); Injection sclerotherapy plus propranolol (1 | 20); Sclerotherapy with ethanolamine (1 |40); Band ligation (2 | 39); Medical management (2 | 110)

Liver fibrosis 1 (60) Praziquantel, anluohuaxian plus interferon gamma (1 | 30); Praziquantel plus “conventional therapy” (1 | 30)

Portal hypertension 5 (327) 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)

Ascites 1 (37) Furosemide, spironolactone plus prednisone (1 | 18); Furosemide plus spironolactone (1 | 19)

Schistosomal 1 (26) Praziquantel plus oxamniquine (1 | 8); Praziquantel, oxamniquine plus prednisolone (1 | 10); Praziquantel, nephropathy oxamniquine plus cyclosporine (1 | 8)

3 (1139) Praziquantel (2 | 386); Praziquantel plus iron (1 | 109); Praziquantel plus micronutrients (1 | 109); Praziquantel plus Anemia related to iron plus micronutrients (1 | 109); Albendazole, praziquantel plus iron (2 | 51); Albendazole plus praziquantel (2 | 51); schistosomiasis Iron (1 | 44); Placebo/no treatment (2 | 280)

13

Hepatosplenomegaly 1 (94) Praziquantel (1 | 94) associated with Schistosoma mansoni infection Leprosy 120 (14772) Tuberculoid / 21 (5303) Rifampin and dapsone (14 | 2299) paucibacillary (PB) Rifampin plus ofloxacin plus minocycline (5 | 1060); Rifampin plus ofloxacin plus minocycline plus clarithromycin (1 | leprosy 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 / 56 (6388) Rifampin, dapsone plus clofazimine (16 | 846) multibacillary (MB) Rifampin, sparfloxacin, clarithromycin plus minocycline (1 | 18); Ethionamide (1 | 25); Prothionamide (2 | 45); leprosy 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)

Claw deformity 1 (50) Early mobilization after surgery (1 | 25); Immobilization after surgery (1 | 25)

Foot drop 1 (24) Early mobilization after surgery (1 | 13); Immobilization after surgery (1 | 11)

14 Leprosy ulcers 10 (517) 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)

Peripheral blood flow 1 (103) M. vaccae (1 | 52); Placebo/no treatment (1 | 51) chronic leprosy

Osteoporosis 1 (23) Risedronate (1 | 12); Placebo/no treatment (1 | 11)

Leprous neuritis / 7 (394) Steroids (4 | 147); Steroids plus surgery (2 | 82); Isaxonine (1 | 15); Ambulatory care (1 | 13); Inpatient care (1 | 13); neuritis in lepra Surgical management (1 | 29); Medical management (1 | 28); Placebo/no treatment (2 | 67) reaction / treatment of nerve impairment / ulnar neuritis

Paucibacillary lepra 1 (335) Rifampin and dapsone (1 | 184); Rifampin (1 | 151) reaction 1 (257) Rifampin, ethionamide plus dapsone or clofazimine (1 | 257) Multibacillary lepra reaction 20 (1378) 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); Erythema nodosum Dapsone plus mefenamic acid (1 | 103); Thalidomide (7 | 136); Pentoxifylline (1 | 24); Clofazimine (2 | 19); Levamisole leprosum / Type 1 plus dapsone (1 | 7); Corticosteroids (7 | 449); Placebo/no treatment (9 | 135); reaction / lepra reaction / ‘lepromatous leprosy reaction’ Filariasis 73 (9996) Albendazole plus ivermectin (8 | 623); DEC plus albendazole (15 | 1953); DEC (44 | 2901) DEC plus doxycycline (1 | 25); Albendazole (8 | 744); Doxycycline (5 | 278); Doxycycline plus albendazole plus ivermectin (2 | 36); Ivermectin (26 | 1388); 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 (20 | 1304) Onchocerciasis 62 (25182) Onchocerca volvulus 53 (10940) Doxycycline plus ivermectin (2 | 150); Ivermectin (27 | 5398) individual treatment 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 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 (27 |4019)

O. volvulus mass control 1 (1625) Ivermectin (1 | 812); Placebo/no treatment (1 | 813) strategy

O. volvulus mass 4 (12489) Ivermectin (4 | 7936); Placebo/no treatment (4 | 4553) treatment and prevention 4 (128) DEC plus prednisone plus cyprohepatidine (1 | 20); DEC (4 |63); DEC plus prednisone (1 | 23); DEC plus indomethacin Diethylcarbamazine (1 | 12); DEC plus cyprohepatidine (1 | 10) (DEC) reaction Trachoma 54 (10420) Active trachoma 29 (5316) Oral azithromycin (8 | 871); Ophthalmic tetracyclines (14 | 1849) 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)

Trachoma mass 15 (1456) Oral azithromycin (7 | 83); Ophthalmic tetracycline (5 | 179) control strategy 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)

Trachomatous dry eye 1 (64) Cyclosporine eye drops (1 | 32); Placebo/no treatment (1 | 32)

Trichiasis 9 (3584) Azithromycin to index patient (1 | 483); Azithromycin to index patient and household contacts (2 | 701); Ophthalmic

16 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) Rabies 45 (6756) Rabies true post- 13 (2129) Purified Vero cell vaccine IM (3 | 399); Purified chick embryo cell vaccine ID (4 | 171); Purified chick embryo cell exposure treatment 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)

Rabies simulated 32 (4627) Chromatographically purified Vero cell vaccine IM (2 | 506); Purified Vero cell vaccine ID (4 | 389); Purified Vero cell exposure or low risk vaccine IM (6 | 503); Purified duck embryo vaccine IM (2 | 236); Purified chick embryo cell vaccine ID (9 | 1297); exposure 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 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 24 (2374) Dengue hemorrhagic 2 (141) Dextran 40 (1 | 57); Haes-Steril (1 | 47); AC-17 plus lactated Ringer’s (1 | 18); Normal saline plus lactated Ringer’s (1 | fever (DHF) 19) resuscitation fluid 6 (890) Lactated Ringer’s (3 | 196); 6% Dextran 70 (4 |260); 6% hydroxylethyl starch (2 | 191); Normal saline (3 | 73); Dengue shock syndrome Haemaccel (1 | 6); Gelafundin (2 | 69); AC-17 (1 | 45); Placebo/no treatment (1 | 50) (DSS) resuscitation fluid 3 (387) Chloroquine (1 | 153); Homeopathic remedy (1 | 29); Calcium carbonate (1 | 10); Placebo/no treatment (3 | 195) Dengue fever (DF) 4 (377) Dexamethasone (1 | 100); Fresh frozen plasma (1 | 53); Intravenous immunoglobulin (1 | 15); WinRho (1 | 25); Thrombocytopenia Placebo/no treatment (4 | 184) associated with DF 1 (114) Doxycycline (1 | 45); Tetracycline (1 | 35); Placebo/no treatment (1 | 34) DF and DHF 1 (25) Recombinant Factor VIIa (1 | 16); Placebo/no treatment (1 | 9) Bleeding associated with DHF 6 (403) Methylprednisone (2 | 43); Hydrocortisone (4 | 149); Placebo/no treatment (6 |211) DSS corticosteroids 1 (37) Oxygen mask (1 | 19); Nasal CPAP (1 | 18) Respiratory failure associated with DSS American Trypanosomiasis 22 (1772) Chronic Chagas disease 8 (1273) Benznidazole (5 | 429); Nifurtimox (1 | 27) Itraconazole (2 | 221); Allopurinol (3 |213); Placebo/no treatment (7 | 383)

Chagas cardiomyopathy 4 (129) ACE inhibitor (2 | 26); Exercise program (1 | 21); Carvedilol (1 | 19); Placebo/no treatment (4 | 63)

Arrhythmias associated 3 (114) Carbamazepine (1 | 8); Flecainide (1 | 40); Amiodarone (1 | 41); Disopyramide (1 | 8); Disopyramide plus amiodarone with cardiomyopathy (1 | 9); Placebo/no treatment (1 | 8)

Cardioneuropathy 1 (58) Cronassial (ganglioside therapy) (1 | 39); Placebo/no treatment (1 | 19)

18

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 3 (181) Praziquantel (3 | 63); Amoscanate (1 | 26); Hexachloroparaxylol (1 | 29); Hexachloroparaxylol plus amoscanate (1 | 22); Placebo/no treatment (2 | 41)

Opisthorchiasis 4 (316) 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)

Paragonimiasis 2 (216) 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) anumber of patients in each section do not add up to total as some trials addressed more than one disease bSolid underlined regimens are recommended 1st line therapies, dotted underlined regimens are recommended 2nd 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 References

1. Bethony J, Brooker S, Albonico M, et al. Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet 2006;367:1521-32.

2. 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;21:673-81.

4. Reithinger R, Dujardin JC, Louzir H, Pirmez C, Alexander B, Brooker S. Cutaneous leishmaniasis. Lancet

Infect Dis 2007;7:581-96.

5. Anonymous. Drugs for Parasitic Infections. Treatment guidelines from The Medical Letter 2007;5

(Suppl):e1-e15.

20