[e-med] Efficacité des combinaisons à base dartémsinine

[marquet.isabelle@wanadoo.fr]

E-MED: Efficacité des combinaisons à base d?artémsinine
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Concernant l?efficacité des combinaisons à base d?artémsinine dans le
traitement du paludisme, vient de paraître dans le « Lancet » du 03/01/04,
deux articles intéressants :
- Artesunate combinations for treatment of malaria : meta-analysis
(International Artemisinin Study Group) ;
- Dihydroartemisinin-piperaquine against multidrug-resistant Plasmodium
falciparum in Vietnam : randomised clinical trial. Tran Tinh Hien et col.

Voici la traduction d?un article de la même édition du Lancet, introduisant
ces deux articles :
http://www.thelancet.com/search/search.isa

Isabelle Marquet

« Les associations thérapeutiques dans le traitement du paludisme : l?heure
des combinaisons à base d?artémisinine ?

Dans l?édition de Janvier du Lancet, un groupe d?étude international fait le
rapport de l?addition d?artésunate aux antipaludiques couramment utilisés.
Cette méta analyse inclus 3 études de Thaïlande, 12 études d?Afrique
subsaharienne et 1 étude du Pérou, pour un total de près de 6000 patients
avec un paludisme simple.
Dans la plupart des études (mais pas toutes), l?addition d?artésunate
diminue significativement les taux de parasitémie à J14 et J28 après le
début du traitement, et réduit le taux de gamétocytes circulant à J7. L?
addition d?artésunate n?a pas engendré d?augmentation d?effets secondaires
graves, comparé au placebo. Cependant, l?utilisation chez la femme enceinte
reste incertaine et doit rester une préoccupation.
Deux ans après que l?OMS se soit prononcée fortement en faveur de la théorie
des associations thérapeutiques dans le traitement du paludisme,  et plus
spécialement des combinaisons d?artémisinine, les résultats du groupe de
travail sur l?artémisinine donnent une nouvel élan en faveur de leur
introduction et d?un changement des traitements de première ligne.
Cependant, les ministres de la santé peuvent raisonnablement demander si les
combinaisons d?artéminsine sont forcément l?étape logique suivante. Les
combinaisons à base d?artésunate sont-elles plus efficaces que les autres
combinaisons ? Cette méta analyse ne répond pas à cette question. Une étude
récente en Ouganda, suggère que l?association amodiaquine-SP est supérieure
à l?association artésunate ?SP pour la prévention des recrudescences
tardives. Amodiaquine-SP est aussi moins chère, et libèrerait ainsi des
lignes  budgétaires pour d?autres priorités de santé publiques dans les pays
pauvres.
Cependant, parce que la résistance des parasites à l?amodiaquine et au SP
sont déjà apparues en Afrique, cette association ne pourrait être utile que
comme stratégie à court terme. De futures études devraient permettre de
comparer les autres associations thérapeutiques, y compris celles sans
dérivés d?artémisinine.
Dans une des ces études, Tran Hien et col, rapportent que la nouvelle
coformulation dihydroartémisine-pipéraquine, est très efficace au Vietnam,
où il existe des résistances multiples. Cette association dont le coût est d
?environ 1 US$ pour un traitement adulte, reste hors de portée de beaucoup
de patients, et encourage les dons des agences internationales pour
sponsoriser ces traitements et les rendre accessibles aux pays les plus
pauvres.
Les combinaisons à base d?artémisinine permettront-elles de réduire l?
incidence du paludisme et d?empêcher la progression des résistances en
Afrique comme cela a été le cas en Asie ?

Il faudra d?autres études pour répondre à cette question. Cependant, réduire
l?incidence du paludisme en Afrique restera un challenge, du fait du profil
épidémiologique et de l?intensité des transmissions.  Alors qu?en Asie, les
individus infectés par le parasite présentent toujours des symptômes, en
Afrique, il existe de nombreux porteurs du parasite asymptomatiques, qui
représentent des réservoirs susceptibles d?entretenir la transmission.

De plus, les résultats des essais de Thaïlande étudiés dans la méta analyse
sont généralement supérieurs aux résultats obtenus dans les autres pays. Les
études Thaï concernent l?association artésunate-méfloquine, une association
qui présente des effets synergiques in vitro sur le plasmodium falciparum.
Reste à savoir si d?autres associations, présenteront la même efficacité sur
la réduction de l?incidence et l?apparition des résistances que
artésunate-méfloquine.

Cette méta analyse apporte la preuve que la progression de la résistance
continue.  L?utilisation des associations thérapeutiques est la suite
logique et urgente pour arrêter ce phénomène. Les associations à base d?
artémisinine ont été supérieures aux monothérapies standards dans la plupart
des résultats en ce qui concerne la parasitémie et le nombre de gamétocytes
circulants. Mais il n?est pas encore possible de déterminer si les
associations à base d?artémisine sont les associations les plus efficaces
dans un pays donné, ni quelle association.

Ainsi, chaque pays pourra faire un choix différent pour la molécule à
utiliser en première ligne.  Ce qui est justement le problème actuellement.
Zanzibar et le Burundi ont récemment adopté l?association artésunate
amodiaquine en première ligne, alors que la Zambie a choisi l?association
artésunate-luméfantrine, et le Rwanda a décidé d?utiliser l?association
amodiquine-SP comme stratégie à court terme.
Ils ont tous décidé d?agir, mais n?ont pas tous opté pour les dérivés d?
artémisinine.
Et si tous les pays décidaient d?adopter les associations à base d?
artémisinine, y aurait il assez de d?artémisinine pour alimenter cet énorme
marché ?
La mise en place d?études de surveillance de l?efficacité de ces molécules
sur le long terme  est urgente, afin de pouvoir définir des stratégies de
traitement basése sur l?EBM en Afrique.
Par exemple, l?East African Network for Monitoring Antimalarial Treatment
est un réseau de sites sentinelles qui produit des informations aux
Ministres de la santé de la région des grands lacs en Afrique. Les autres
sous régions devraient mettre en place de tels réseaux. La vie de million de
gens en dépend. »


***************
The Lancet
Volume 363, Number 9402     03 January 2004
http://www.thelancet.com/search/search.isa

Drug combinations for malaria: time to ACT?

The scientist and popular writer Robert Desowitz calls malaria "the oldest
emerging disease". Malaria is certainly old: the written records of the
earliest human civilisations describe the distinct periodic fevers. From the
vantage point of populations suffering under the burden of malaria, the
thought that malaria might also be emerging or re-emerging is frightening
but accurate. Despite its already enormous toll of human suffering, deaths
due to malaria are increasing. A major factor contributing to the resurgence
of malaria is drug resistance. For 50 years after its discovery, chloroquine
was a cheap, safe, and effective oral drug for malaria in Africa. In many
parts of Africa, chloroquine is no longer effective because of
chloroquine-resistant parasites that are spreading rapidly throughout the
remainder of the continent. Sulfadoxine-pyrimethamine is the most feasible
and economical alternative, but its effiectiveness declined precipitously
after it was introduced as first-line therapy in several African countries
over the past decade.

Ironically, the best new medicine for malaria is one of the oldest.
Artemesinin (qinghaosu) is the antimalarial extract of Artemesia annua
(sweet wormwood) that has been used for centuries in traditional Chinese
medicine to cure fevers. First isolated in 1971 by Chinese chemists,
artemisinin is a sesquiterpene lactone with a peroxide group, and is
chemically unrelated to quinine or other existing antimalarial agents.
Artemisinin and its derivatives, artemether and artesunate, can clear
parasitaemia and reverse coma more rapidly than other drugs,1 but parasite
recrudescence is common after monotherapy unless treatment is extended to 7
days.2

In southeast Asia, an epicentre for drug-resistant malaria, artemisinin
combination treatment (ACT), particularly artesunate-mefloquine, has been a
highly effective, safe, and durable regimen. Provision of
artesunate-mefloquine as standard therapy in western Thailand and Vietnam
has coincided with the reduced incidence of falciparum malaria and the
stabilisation or reversal of mefloquine-resistance rates.3 The reduced
incidence of malaria and the containment of resistant parasites have been
attributed to the ability of artesunate to kill gametocytes,4 the forms of
parasite that infect mosquitoes, and thereby reduce transmission. Can Africa
anticipate similar benefits by deploying ACT?

In today's Lancet, the International Artemisinin Study Group reports on the
addition of artesunate to standard antimalarial drugs. This
individual-patient meta-analysis includes three studies from Thailand,
twelve studies from sub-Saharan Africa, and one from Peru: a total of nearly
6000 patients with uncomplicated malaria. In most studies (but not all), the
addition of artesunate significantly increased parasite clearance rates at
days 14 and 28 after treatment, and reduced gametocyte carriage rates at day
7. Reassuringly, the addition of artesunate showed no increase in severe
adverse events above the rate seen with placebo. Nonetheless, the safety of
artemisinins during pregnancy remains unclear and a great worry.5

2 years after WHO gave its strong endorsement to combination therapy,
especially ACT in Africa, the results from the International Artemisinin
Study Group give further impetus to implementing a change in first-line
therapy. However, ministers of health could reasonably ask whether ACT is
the logical next step. Are combinations with artesunate superior to other
drug combinations? The new meta-analysis does not answer this question. A
recent study in Uganda suggested that amodiaquine-sulfadoxine-pyrimethamine
was superior to artesunate-sulfadoxine-pyrimethamine for preventing late
recrudescences.6 Amodiaquine-sulfadoxine-pyrimethamine is also much cheaper,
and thus would free resources for other pressing health needs in poor
countries.

However, because parasite resistance to amodiaquine and
sulfadoxine-pyrimethamine has already appeared in Africa, this combination
may only be useful as a short-term strategy. Future studies should compare
other drug combinations, including those without artemisinins. In one such
study, also reported today, Tran Hien and colleagues found that the new
combination of dihydroartemisinin-piperaquine, formulated in a single
tablet, is highly efficacious in Vietnam, where multidrug-resistant
parasites are common. Dihydroartemisinin-piperaquine has a cost advantage
(US$1 for an adult treatment) that brings it within reach of many but not
all consumers, and encourages funding agencies to sponsor programmes that
deliver these needed medicines to poorer countries.

Will ACT reduce malaria incidence and prevent the emergence and spread of
drug-resistant parasites in Africa, as occurred in southeast Asia? Only
additional research will answer these questions. However, because of
differences in epidemiology and intensity of transmission, reducing malaria
incidence in Africa will be challenging. Whereas infected individuals in
Thailand usually become symptomatic, many Africans carry heavy infections
without symptoms and thus act as a reservoir for continued transmission of
parasite. Further, the results from the Thai studies in today's report by
the Artemisinin Group were generally superior to the results from other
countries. The Thai studies exclusively examined mefloquine-artesunate, a
combination that demonstrates potentiative synergism in vitro against
Plasmodium falciparum.7 Whether other ACT formulations will equal
mefloquine-artesunate in reducing malaria incidence and containing the
spread of resistant parasites remains to be seen.

Today's meta-analysis provides compelling evidence that drug-resistant
malarial parasites are continuing their inexorable global march. Combination
therapy is a logical (and urgent) next step to slow this alarming state of
affairs. ACT was superior to standard monotherapy in most settings where it
was evaluated for reducing parasitaemia and gametocytaemia. Whether (or
which) ACT is the best combination therapy for first-line treatment in a
particular country has not been adequately studied. Under the circumstances,
different countries could reasonably make different choices for first-line
therapy--which is precisely the current state of affairs. Zanzibar and
Burundi have recently adopted artesunate-amodiaquine as first-line therapy,
Zambia has adopted artesunate-lumefantrine, and Rwanda has adopted
amodiaquine-sulfadoxine-pyrimethamine as a short-term strategy. These
countries have each decided to act, but not all have chosen ACT. And if all
countries were to deploy ACT in the near future, is there sufficient
artemisinin to supply this enormous market?

Long-term surveillance studies are essential to guide evidence-based
antimalarial treatment policies throughout Africa and elsewhere. For
example, the East African Network for Monitoring Antimalarial Treatment8
operates a network of sentinel sites and provides timely information on
treatment efficacy to health ministries throughout the Great Lakes region of
Africa.9 Other sub-regions should adopt a similar model. Millions of lives
depend on it.

TKM is head of the East African Network for Monitoring Antimalarial
Treatment.
*Patrick E Duffy, Theonest K Mutabingwa



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----
Malaria Antigen Discovery Program, Seattle Biomedical Research Institute,
Seattle, WA 98109, USA (PED); Department of Immunology, Walter Reed Army
Institute of Research, Silver Spring, Maryland, (PED); Gates Malaria
Partnership, London School of Hygiene and Tropical Medicine, London, UK
(TKM); and National Institute for Medical Research, Dar es Salaam, Tanzania
(TKM) (e-mail:patrick.duffy@sbri.org)

1 Klayman, DL. Qinghaosu (artemisinin): an antimalarial drug from China.
Science 1985; 228: 1049-55. [PubMed]

2 Nguyen DS, Dao BH, Nguyen PD, et al. Treatment of malaria in Vietnam with
oral artemisinin.  Am J Trop Med Hyg 1993; 48: 398-402. [PubMed]

3 Nosten F, van Vugt M, Price R, et al. Effects of artesunate-mefloquine
combination on incidence of Plasmodium falciparum malaria and mefloquine
resistance in western Thailand: a prospective study.  Lancet 2000; 356:
297-302. [Text]

4 Kumar N, Zheng H. Stage-specific gametocytocidal effect in vitro of the
antimalaria drug qinghaosu on Plasmodium falciparum.  Parasitol Res 1990;
76: 214-48. [PubMed]

5 WHO. Assessment of the safety of artemisinin compounds in pregnancy:
report of two informal consultations convened by WHO in 2002 (Roll Back
Malaria and the UNDP/World bank/WHO Special Programme for Research and
Training in Tropical Diseases). WHO: Geneva, 2003:
www.who.int/tdr/publications/publications/pdf/ artemisinin-pregn.pdf
(accessed Dec 1, 2003).

6 Dorsey G, Njama D, Kamya MR, et al. Sulfadoxine/pyrimethamine alone or
with amodiaquine or artesunate for treatment of uncomplicated malaria: a
longitudinal randomised trial.  Lancet 2002; 360: 2031-38. [Text]

7 Chawira AN, Warhurst DC. The effect of artemisinin combined with standard
antimalarials against chloroquine-sensitive and chloroquine-resistant
strains of Plasmodium falciparum in vitro.  J Trop Med Hyg 1987; 90: 1-8.
[PubMed]

8 EANMAT. East African Network for Monitoring Antimalarial Treatment. May
29, 2003: http://www.eanmat.org (accessed Dec 1, 2003).

9 The East African Network for Monitoring Antimalarial Treatment (EANMAT).
The efficacy of antimalarial monotherapies, sulfadoxine-pyrimethamine and
amodiaquine in East Africa: implications for sub-regional policy.  Trop Med
Int Health 2003; 8: 860-68. [PubMed]

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