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The latest evidence from large scale clinical trials

LeishmaniaLeishmania isis not not an an approved approved indication indication for Liposomal for Liposomal Amphotericin in Italy B in Italy Update on treatment of Indian visceral

Shyam Sundar Banaras Hindu University India S Sundar, ECCMID 2011 Treatment seeking behaviour of patients with VL

Qualified 27% <30 30 days Quacks days 73%

First contact Duration of treatment

Adequate Irregular 26% 42% Regular 58%

Inadequate 74%

Regularity of treatment Dose & duration

S Sundar, ECCMID 2011 Sundar S et al. BMJ 1994;308(6924):307. Sundar S, personal communication. Decreasing (SSG) efficacy

Efficacy of SSG 20 mg/kg/d in Bihar, India during 1988-2002.

100

80

60

40 % cured %

20

0 1988 1990 1992 1994 1996 1998 2000 2002

S Sundar, ECCMID 2011 Olliaro PL et al. Lancet Infect Dis 2005;5:763–74. Sundar S, personal communication.

• Paromomycin sulfate is an , several phase II studies done in India & Africa1 • Phase III study was done (n=501) at a dose of 15 mg/kg/day for 21 days2 • The drug was well tolerated, there was no nephrotoxicity2 . Reversible (n=7, 2%) . High overall cure rates (final cure: 94.6%) . Effective in Sbv/ therapy failed patients . Produced in India, cost of a full adult treatment, $15 US3 • In phase 4 study these findings were replicated3

S Sundar, ECCMID 2011 1. Musa AM et al. PLoS Negl Trop Dis 2010;26:e855. 2. Sundar S et al. NEJM 2007;356:2571–81; 3. Sundar S, personal communication. Paromomycin (licensed in 2006)

• Pros and Cons

. Cheapest1

. Can be used as outpatient therapy2

. Suitable for women3 (no known teratogenicity)

. Manufactured in India3

. 21 intramuscular injections!3

. Has to be delivered as Directly Observed Therapy (DOT)

. Hepatotoxicity in a small proportion of patients3

. Aminoglycoside3 (prone to develop resistance4)

1. Sundar S & Rai M. Expert Opin Pharmacother 2005;6(16):2821–2829; 2. Olliaro P et al. Trop Med Int Health. 2009;14:918–925; 3. Sundar S et al. NEJM 2007;356:2571–81; S Sundar, ECCMID 2011 4. Croft et al. Clin Microb Reviews 2006;19:111–126. Miltefosine

• Hexadecylphosphocholine (alkylphospholipid analogue)1

• Developed as an oral antineoplastic agent, but GI adverse events limited its use1,2

• Excellent anti-leishmanial activity in experimental animals and in vitro2

• A pilot dose escalating study conducted in 19972

S Sundar, ECCMID 2011 1. Hilgard P et al. Eur J Cancer 1997;33:442–446; 2. Sundar S et al. Lancet 1998;352:1821–23. Initial & final cure

Dose groups Apparent Definite Adverse events cure cure day 28 8 months 50 mg/alt day 5 2 Mild

100 mg/alt day 5 1 Mild

100 mg/day 5 5 Mild - Mod

150 mg/day 5 4 Mild - Mod

200 mg/day 5 5 Mod - Severe

250 mg/day 4 4 Severe

S Sundar, ECCMID 2011 Sundar S et al. Lancet 1998;352:1821-23. Sundar S, personal communication. Miltefosine phase I & II trials – results (including 1 multicenter trial)

Daily dose Patients Definite cure 28 days (n) % ~100 mg 100 97 97

~150 mg 53 51 96

>200 mg 19 19 100

100 mg x 21 days 18 18 100

100 mg x 14 days 18 16 89

Sundar S et al. Clin Infect Dis 2000;31:1110–1113; Sundar S et al. NEJM 1999;341:1795–1800; S Sundar, ECCMID 2011 Sundar S et al. Ann Trop Med Parasitol 1999;93(6):589–597. Sundar S, personal communication. Miltefosine – conclusions

• Dose: 100 mg (>25 kg); 50 mg (<25 kg);1 children 2.5 mg/kg2 • Duration: four weeks1 • Side – effects:1 . Vomiting occurs in ~40% . Diarrhea in ~20% . Transient elevation of hepatic enzymes . Skin allergy, are occasionally seen • Long term cure rates 94%1 • Cannot be used in pregnant females [teratogenic3], and those refusing contraception (for the treatment period and another three months)1

S Sundar, ECCMID 2011 1. Sundar S. NEJM 2002;347:1739–1746; 2. Sundar S & Chatterjee M. Indian J Med Res 2006;123:345–352; 3. Sindermann H & Engel J. Trans Royal Soc Trop Med Hyg 2006;100S:S17–S20. S Sundar, ECCMID 2011 Sundar S, personal communication ORAL MILTEFOSINE vs CONVENTIONAL AMPHOTERICIN B

LEUCOCYTE AND HEMOGLOBIN

(leu)

3 3

/mm

9

mg/L (Hb) (Hb) mg/L x10

S Sundar, ECCMID 2011 Sundar S, personal communication Miltefosine (licensed in 2002) • Miltefosine was chosen as drug for VL elimination programme in India, Nepal and Bangladesh • Pros and cons – Big oral advantage1 – Easy to implement in programme BUT – 28 days treatment1 – Teratogenic2 – ~2% severe adverse events1 (lab monitoring?) – In a recent evaluation we found 20-33% patients discontinued therapy3 – Long half life (rapid emergence of resistance)1 – May lose this important drug in next few years

S Sundar, ECCMID 2011 1. Sundar S et al. Trop Med Int Health 2008;13:2–5; 2. Sindermann H & Engel J. Trans Royal Soc Trop Med Hyg 2006;100S:S17–S20. 3. Sundar S personal communication. Conventional amphotericin B

• Polyene antibiotic1 • Dose 0.75–1.0 mg/kg daily or alternate days for 15–20 infusions1,2 • Infusion reactions, thrombophlebitis common1 • Hypokalemia, myocarditis & death are serious, but uncommon, toxicities1 • High cure rates >97% at 6 months2

1. Sundar S. Med Mecrobiol Immunol. 2001;190:89–92; 2. Sundar S et al. CID 2003;37:800–4. S Sundar, ECCMID 2011 S Sundar, ECCMID 2011 Lipid associated amphotericin B in VL

• Most exciting development

• Targeted delivery to macrophages1

• Possible to infuse high dose in short duration as compared to 5–6 weeks of conventional treatment2

• Low toxicity3/improved potency2

• Highly expensive2

• Liposomal (AmBisome), lipid complex (Abelcet) and colloidal dispersion (Amphocil) now available3

1. Davidson RN et al. Quarterly Journal of Medicine 1994;87:75–81; 2. Sundar S et al. CID S Sundar, ECCMID 2011 2003;37:800–4; 3. Du Pont B. Brit Soc Antimicrob Chemo 2002;49:31–36. Liposomal amphotericin B (AmBisome) in refractory Indian VL

Total dose No. of Treatment Cure Author mg/kg patients duration rate 14 10 Day 1-6, 10 100 Thakur, 10 10 Day 1-4, 10 100 19961 6 10 Day 1, 5, 10 100 15 28 5 96 Sundar, 7.5 28 5 93 20022 3.75 28 5 89

1. Thakur et al. Trans R Soc Trop Med Hyg. 1996;90(3):319–322; S Sundar, ECCMID 2011 2. Sundar et al. Am J Trop Med Hyg. 2002;66:143–146. Conventional and lipid amphotericin B in the treatment of ______Ampho B AmBisome ABLC ______Total dose (mg/kg) 15 10 10 Daily dose *1 mg/kg 2 mg/kg 2 mg/kg No. patients enrolled 51 51 51 Died during treatment 2 0 0 Failed treatment 0 1 0 Initial cure 49 50 51 Relapses 0 1 4 Final cure 49 (96%) 49 (96%) 47 (92%) 95% CI (85–100) (85–100) (80–98) ______*Alternate day infusions

S Sundar, ECCMID 2011 Sundar S et al. Clin Infect Dis 2004;38:377-83. Infusion-associated reactions with amphotericin B & its lipid formulations ______Ampho B AmBisome ABLC ______

Patients (n) 51 51 51

No reaction 1 (2%) 36 (71%) 12 (24%)

Fever and/or rigors 50 (98%) 15 (29%) 39 (76%)

Episodes per patient 8.4 + 0.3 0.6 + 0.1 1.4 + 0.1

P<0.05 for all values for the Ampho B group vs the AmBisome group or ABLC group, and for all values for the AmBisome group vs the ABLC group.

Sundar S et al. Clin Infect Dis 2004;38:377–83. S Sundar, ECCMID 2011 Single dose liposomal amphotericin B (AmBisome) in Indian VL

Total dose No. of Treat. Cure rate mg/kg patients* dur.

5 46 1 91 (Sundar, 2001)1*

5 45 5 93 (Sundar, 2001)1*

7.5 203 1 90 (Sundar 2003)2*

15 17 1 100 (Thakur 2001)3

* Multicentre

S Sundar, ECCMID 2011 1. Sundar S et al. BMJ. 2001; 323: 419–22; 2. Sundar et al. Clin Infect Dis. 2003;37:800–804; 3. Thakur CP et al. J Antimicrob Agents. 2001;17:67–70. Why liposomal ampho B (AmBisome) now?

• Highly expensive earlier beyond reach of developing countries1

• However, WHO entered into an agreement with Gilead for preferential pricing to supply AmBisome at $20 US/vial of 50 mg in 20071

• Now AmBisome is available for VL through WHO at 9% of its original price ($18/vial)2

S Sundar, ECCMID 2011 1. Sundar S et al. NEJM 2010;362:504–12. 2. Gilead, data on file Single-dose liposomal amphotericin B for visceral leishmaniasis in India

• Efficacy of a single infusion of 10 mg/kg of liposomal amphotericin B (AmBisome)

vs

• Conventional parenteral therapy, consisting of 15 alternate day infusions of amphotericin B deoxycholate

S Sundar, ECCMID 2011 Sundar S et al. NEJM 2010;362:504–12. Results

• Of the 412 pts, 80 had undergone previous treatment

• 410 pts completed their assigned treatment, and on day 30, all had apparent cure

• No patient was lost to follow up

• No serious adverse events were reported in either group

• Sypmtomatic relapse of occurred in 15 patients

S Sundar, ECCMID 2011 Sundar S et al. NEJM 2010;362:504–12. Efficacy of single dose liposomal amphotericin B

Response to Treatment (10 mg/kg) Liposomal Amphotericin B Variable Amphotericin B Deoxycholate (N = 304) (N = 108) Removed from study — no. 0 2 Completed treatment — no. 304 106 Apparent cure at day 30 — no. 304 106 Relapse — no. (%) 13 (4.3) 2 (1.9) Lost to follow-up — no. 0 0 Definitive cure at 6 months Intention-to-treat population Intention-to-treat population 291 104 Percent (95% CI) 95.7 (93.4–97.9) 96.3 (92.6–99.9) Per-protocol population No. of patients 291 104 Percent (95% CI) 95.7 (93.4–97.9) 98.1 (95.5–100.0)

S Sundar, ECCMID 2011 Sundar S et al. NEJM 2010;362:504–12. Cost comparison

• In India, liposomal amphotericin B can be available at $18 per vial,1 and the retail cost of amphotericin B deoxycholate is $6.50 per 50 mg vial2

• The total cost of a single infusion of liposomal therapy for a 35 kg pt would be $148 ($134 for an outpatient)1

• For a similar patient, 15 alternate-day infusions of amphotericin B deoxycholate during a 30-day hospital stay would be $4362

S Sundar, ECCMID 2011 1. Gilead, data on file 2. Sundar S et al. NEJM 2010;362:504–12. Conclusions – Single Dose AmBisome

• A single infusion of liposomal amphotericin B was not inferior to and was less expensive than conventional therapy with amphotericin B deoxycholate

• Not associated with any safety concern in adults or children

• Compliance is guaranteed

• Amenable for use at peripheral health facilities

• Minimal hospital stay and cost effective

S Sundar, ECCMID 2011 Sundar S et al. NEJM 2010;362:504–12. COMBINATION THERAPY IN VL

S Sundar, ECCMID 2011 What is the rationale of combination?

• Every drug with the exception of amphotericin B is prone to development of resistance • No new drug in pipeline • The only way to protect the newly developed drugs is to develop combination chemotherapy . Shorten duration . Better compliance . Reduce costs; improve cost-effectiveness . Less chances of development of drug resistance . Reduce drug pressure; mutual protection against resistance  prolong therapeutic life-span of effective use • Safety and efficacy data in animals support use of combination therapy

Sundar S personal communication. S Sundar, ECCMID 2011 Results of a phase II combination trial in Indian VL

Initial Final 95% Regimen n cure cure confidence rate (%) rate interval AmBisome (5 mg/kg) 45 100 91 78–97

AmBi 5 + Milt 14 days 45 100 96 84–99 AmBi 3.75 + Milt 45 100 96 84–99 14 days AmBi 5 + Milt 10 days 46 100 98 87–100

AmBi 5 + Milt 7 days 45 100 98 87–100

Sundar S et al. CID 2008;47:1000–6. S Sundar, ECCMID 2011 Phase 3 short-course combination treatment for VL in India

• A randomized, controlled, non-inferiority trial of 3 different combinations versus a standard treatment with amphotericin B • Powered for expected cure rate of 97% for standard and Δ= -7% between each combination and ampho B • Treatments: . Standard treatment: 15 amphotericin B infusions 1 mg/kg alternate days for 30 days . Single infusion of 5 mg/kg liposomal amphotericin B (L-AmB) on D1 followed by 7-days oral miltefosine . Single infusion of 5 mg/kg L-AmB on D1 followed by 10-day paromomycin . Miltefosine and paromomycin for 10 days

S Sundar, ECCMID 2011 Sundar S et al. Lancet 2011;377:477–86. Most frequent adverse events

AmphoB AmB-5 +M AmB-5+P M+P

Diarrhea 3 (2%) 3 (2%) 1 5 (3%) Vomiting 30 (19%) 25 (16%) 5 (3%) 16 (10%) Asthenia 1 3 (2%) 2 (1%) 3 (2%) Chills 113 (72%) 20 (13%) 20 (13%) 0 Injection site pain 0 0 10 (6%) 14 (9%) Pyrexia 37 (24%) 31 (19%) 33 (21%) 32 (20) Increased creatinine 15 (10%) 1 6 (4%) 6 (4%)

Treatment was withdrawn in 7 patients in ampho B group (5 nephrotoxicity, 1 hepatotoxicity, 1 deterioration of clinical condition)

S Sundar, ECCMID 2011 Sundar S et al. Lancet 2011;377:477–86. Hb evolution over time in each treatment arm

13 Ampho B 3a 12 AmB-5 + Milt-7 AmB-5 + Paro-10 Milt-10 + Paro-10 11

10

9

8

Haemoglobin (g/dl) Haemoglobin

7

6

0 Baseline Day 7 Day 15/31 Day 45 Days

S Sundar, ECCMID 2011 Sundar S et al. Lancet 2011;377:477–86. Creatinine evolution over time in each treatment arm

1.4 3b Ampho B AmB-5 + Milt-7 AmB-5 + Paro-10 1.2 Milt-10 + Paro-10

1.0

0.8

Creatinine (mg/dl) Creatinine

0.6

0.0 Baseline Day 7 Day 15/31 Day 45 Days

S Sundar, ECCMID 2011 Sundar S et al. Lancet 2011;377:477–86. Efficacy: high definitive cure rates

Definitive cure at 6 AmB-5+ AmB-5+ Milt-10+ Ampho B Months Milt-7 Paro-10 Paro- 10 All randomised population 157 160 158 159 (N=634) No. of patients cured 146 156 154 157 Percent 93.0% 97.5% 97.5% 98.7% [95% CI] [88-96] [93-99] [93-99] [95-100] Per-protocol population 148 157 155 158 (N=618) No. of patients cured 146 155 153 156 Percent 98.6% 98.7% 98.7% 98.7% [95% CI] [95-100] [95-100] [95-100] [95-100]

S Sundar, ECCMID 2011 Sundar S et al. Lancet 2011;377:477–86. Therapeutic options ranked by preference (for Bangladesh, Bhutan, India and Nepal) 1. Liposomal amphotericin B (single or multiple infusions) 2. Combination therapy using – liposomal ampho B with miltefosine – liposomal ampho B with paromomycin – paromomycin with miltefosine 3. Amphotericin B infusions (15–30 days) 4. Miltefosine alone, or paromomycin 5. Pentavalent antimonials (daily for 30 days) in areas where they remain effective: Bangladesh, Nepal and the Indian states of Jharkhand, West Bengal and Uttar Pradesh

S Sundar, ECCMID 2011 WHO TRS 949. Control of the Leishmaniases, 2010. Thank you

37 S Sundar, ECCMID 2011