The burden of Neglected Diseases : resistance to drugs or resistance to care about the health of the poor?

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Camilla Watson
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1 Medicinal Chemistry in Parasitology Modena, 23 January 2004 The burden of Neglected Diseases : resistance to drugs or resistance to care about the health of the poor? Zeno Bisoffi, Centro per le Malattie Tropicali, Ospedale Sacro Cuore, Negrar (Verona) Global Burden of Infectious Diseases Infectious Diseases = 32% of Total Global Deaths Infectious Diseases = 68% of deaths in Africa WHO,WHR,

Zeno Bisoffi, Centro per le Malattie Tropicali, Ospedale Sacro Cuore, Negrar (Verona) Global Burden

2 Neglected diseases Neglect = to give not enough care or attention to something that is of your responsibility Health Burden of Malaria million febrile infections/year million deaths/year, >75% African children <20% come to attention of the health system WHO 2

400-900 million febrile infections/year 0.7-2.

3 Plasmodium life cycle 3

4 4

5 Clinical features Fever Malaise and headache Chills and sweating Myalgia Uncomplicated malaria Uncomplicated malaria is not immediately life threatening but must be treated promptly (failure to diagnose and treat uncomplicated malaria can rapidly lead to severe malaria) 5

immediately life threatening but must be treated promptly (failure

6 The central pathological features of severe malaria are: Sequestration of parasitised erythrocytes in the microvasculature of the brain and other internal organs Local effect of proinflammatory citokines produced in excess (TNF, IL2 Severe malaria impaired consciousness / unrousable coma respiratory distress (acidosis) acute renal failure pulmonary oedema (radiological) abnormal bleeding severe normocytic anemia (Hg < 5 g/dl) 6

in excess (TNF, IL2 Severe malaria impaired consciousness / unrousable coma respiratory distress (acidosis)

7 Severe falciparum malaria Who is mostly at risk children 1-3 years in hyperendemic areas adults and elderly children in ipoendemic areas travellers from non endemic areas pregnant women Triggering factors: Delayed diagnosis Delayed treatment History and frustration of malaria control 1955: Global Malaria Eradication Campaign (W.H.O.): insecticide spraying 1955: first report of dieldrin resistance in Nigeria Mass chemotherapy (chloroquine, pyrimethamine, medicated salts) Rapid spread of resistance (>> pyrimethamine) 7

frustration of malaria control 1955: Global Malaria Eradication Campaign (W.H.O.

8 ACTUAL STRATEGIES OF MALARIA CONTROL Permethrin impregnated bed nets PLUS timely access to effective treatment History of malaria chemotherapy 162 BC - Artemisinin 1712 Torti describes the specific action of the cinchona bark on intermittent fevers (probably known for centuries by incas) 1920s - Primaquine 1930s - Pyrimethamine 1940s Chloroquine, Proguanil Late 1940s - Amodiaquine 1950s Sulfadoxine, Atovaquone Doxicycline 1970s WRAIR identifies WR as a suitable antimalarial 1980s WRAIR identifies halofantrine as an antimalarial agent 2000s Artemisinin, once again 8

1920s - Primaquine 1930s - Pyrimethamine 1940s Chloroquine, Proguanil Late 1940s - Amodiaquine 1950s Sulfadoxine, Atovaquone 1966 - Doxicycline

9 Resistance to antimalarial drugs Chloroquine 16 years Fansidar 6 years Mefloquine 4 years Atovaquone 6 months Barry R. Bloom, 2001 Resistance to antimalarial drugs: CLQ, SP R to chloroquine:mutation of pfcrt gene Starting frequency very low Replaced quinine before significant R to quinine was observed R to SP: mutation of DHFR and/or DHPS Starting freq much higher, faster spread of R 9

Bloom, 2001 Resistance to antimalarial drugs: CLQ, SP R to chloroquine:mutation of pfcrt gene Starting

10 Resistance to antimalarial drugs: quinine Very difficult to select for R in vitro Several genes required Starting freq exceedingly low quinine Quinine still very effective vs. virtually all African isolates First choice in imported malaria Problems of compliance (7 days) 3 d. course plus SP equally effective Only weapon for severe malaria until recently 10

virtually all African isolates First choice in imported malaria Problems of compliance (7

11 Artemisinin derivatives Similarly to quinine, very difficult to select for R in vitro (multiple genes required?) Association should keep the starting freq of R even lower Actual strategy: combination therapies Rationale: starting freq of R strains Drug A freq 0.005%, Drug B % then: A+B 0.005x = % Constraint: COST!!! 11

) Association should keep the starting freq of R even lower Actual strategy:

12 Research needs Fixed-dose, short term combinations (increase compliance) Safe in pregnancy Drugs with multiple effects on the parasite metabolism (more mutations required for R) Truly neglected diseases African trypanosomiasis ( sleeping sickness ) American trypanosomiasis ( Chagas ) Visceral leishmaniasis ( Kala azar ) Only injectable drugs, long treatment Serious side effects Lack of any effective treatment (Chagas) 12

African trypanosomiasis ( sleeping sickness ) American trypanosomiasis ( Chagas ) Visceral leishmaniasis

13 Visceral leishmaniasis ( Kala azar ) estimated 60 thousand deaths per year Visceral leishmaniasis ( Kala azar ) Zoonosis (difficult control): dogs reservoir of L. infantum in Italy In India man only significant reservoir (good news) but: failures of antimonials known for > 20 years R now widespread 13

14 Visceral leishmaniasis ( Kala azar ) Pentavalent antimonials: long, parenteral treatment, high toxicity, R Alternatives: amphotericin B (toxic), lipid associated amphotericin B (out of reach) Miltefosine (tolerated, orally administerd) in phase IV trial: but long half life and teratogenic potential Visceral leishmaniasis ( Kala azar ): future drugs Aminosidine (an aminoglycoside): promising and extensively studied, production stopped by manufacturer Sitamaquine oral compound but slow development, still in phase I-II Other?? Shift to combination treatment to delay R? 14

teratogenic potential Visceral leishmaniasis ( Kala azar ): future drugs Aminosidine (an aminoglycoside): promising and extensively studied,

15 American trypanosomiasis First cause of cardiovascualr deaths in endemic areas os Latin America Virtually untreatable disease (both nifurtimox and benzimnidazole only effective in acute phase, but acute phase almost never diagnosed!) African trypanosomiasis: epidemiology Source: W.H.O

benzimnidazole only effective in acute phase, but acute phase almost

16 African trypanosomiasis: epidemiology Source: W.H.O. at least 50 thousand deaths per year African trypanosomiasis: clinical features late stages T. gambiense severe wasting somnolence CNS signs both forms are always fatal without treatment 16

trypanosomiasis: clinical features late stages T.

17 African trypanosomiasis: treatment of neurological phase if evidence of CNS involvement: melarsoprol (Mel B) Introduced in 1949!! drug-related mortality up to 5%!! uncertainty about diagnosis may lead to death from unnecessary treatment!! relapses may occur African trypanosomiasis: treatment of neurological phase Eflornithine (1979: from oncologic research) First used for A.T. in 1981 Much better tolerated Only drugs for MelB failures Withdrawn from the producing firm for economic reasons in late 90ies!!! 17

! relapses may occur African trypanosomiasis: treatment of neurological phase Eflornithine (1979: from oncologic research) First

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19 Eflornithine story Now re-introduced for AT Oral formulation being tested And that's wonderful news! How shall we treat A.T. in the future?? Anti-helmintic drugs Virtually all come from veterinary research!! R not widespread (most data from vet medicine ) Good example of lack of access/availability (schistosomiasis alone: 15,000 deaths/year, despite praziquantel effective at single dose!) 19

? Anti-helmintic drugs Virtually all come from veterinary research!

20 Concluding remarks Real risk to be left without any effective treatment for many parasitic diseases R&D of orphan drugs cannot be left entirely to the God Market Public responsibility of rich countries, if we still think that health is a Human Right 20

cannot be left entirely to the God Market Public

Nige g ri e an a N at a ional a Antimal a ari a a Tre re t a men e t g ide d l e ines

Nige g ri e an a N at a ional a Antimal a ari a a Tre re t a men e t g ide d l e ines Nigerian National Antimalaria Treatment guidelines Pre Purpose: To provide guidelines for the treatment of malaria in Pregnant women in Nigeria Pregnant women Malaria: An infectious disease caused by plasmodium.