E-drug: Antimalarial cocktails
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[From this weeks Lancet (www.lancet.com): summary of a study from Uganda and
a commentary to this study as well as to the use of combination therapy for
malaria in general. Copied as fair use. KM]
Lancet 2002: 360: 2031-38 (21/28 December)
Sulfadoxine/pyrimethamine alone or with amodiaquine or artesunate for
treatment of uncomplicated malaria: a longitudinal randomised trial. Grant
Dorsey, Denise Njama, Moses R Kamya, Adithya Cattamanchi, Daniel Kyabayinze,
Sarah G Staedke, Anne Gasasira, Philip J Rosenthal
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Department of Medicine, San Francisco General Hospital, University of
California, San Francisco, CA, USA (G Dorsey MD, A Cattamanchi BA, S G
Staedke MD, P J Rosenthal MD); Makerere University Medical School, Kampala,
Uganda (D Njama MBChB, M R Kamya MMed, D Kyabayinze MBChB, A Gasasira MBChB)
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Correspondence to: Dr Grant Dorsey, Department of Medicine, San Francisco
General Hospital, 1001 Potrero Avenue, Building 30, Room 421, San Francisco,
CA 94110, USA (e-mail:grantd@itsa.ucsf.edu)
Summary
Background: New antimalarial treatments are urgently needed in sub-Saharan
Africa. Improved therapies should decrease failure rates in the short term,
but their effect on incidence of subsequent episodes of malaria is little
studied. We aimed to compare the short-term and long-term effectiveness of
three antimalarial regimens in children from Kampala, Uganda.
Methods: We randomly allocated healthy children aged 6 months to 5 years to
receive 25 mg/kg sulfadoxine and 1�25 mg/kg pyrimethamine plus either
placebo, 25 mg/kg amodiaquine, or 12 mg/kg artesunate. Participants were
followed up for 1 year and received the same preassigned treatment for every
new episode of uncomplicated malaria diagnosed during follow-up.
Recrudescent and new infections were distinguished by comparison of
polymorphisms in merozoite surface protein 2 (MSP2). Our primary endpoint
was the total number of treatments for malaria per time at risk. Analyses
were done per protocol.
Findings: 183 (61%) of 316 participants were diagnosed with at least one
episode of uncomplicated malaria. A total of 577 episodes of uncomplicated
Plasmodium falciparum malaria were treated with study drugs; all regimens
were safe and well tolerated. Clinical treatment failure after 14 days was
significantly more frequent in the sulfadoxine/ pyrimethamine group (38 of
215, 18%) compared with either the sulfadoxine/pyrimethamine plus
amodiaquine group (two of 164, 1%; p<0�0001) or sulfadoxine/pyrimethamine
plus artesunate group (one of 198, 1%; p<0�0001). After 28 and 42 days,
patients in the sulfadoxine/pyrimethamine plus amodiaquine group were
significantly less likely to develop malaria than were those in the other
groups. Overall, sulfadoxine/pyrimethamine plus amodiaquine reduced the rate
of subsequent treatments for malaria by 54% (95% CI 36-66, p<0�0001)
compared with sulfadoxine/ pyrimethamine alone and by 37% (12-54, p=0�007)
compared with sulfadoxine/pyrimethamine plus artesunate.
Interpretation: Sulfadoxine/pyrimethamine plus amodiaquine could be used as
an inexpensive regimen to decrease the rate of subsequent episodes of
malaria.
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Lancet 2002; 360: 1998-9 (21/28 December)
Commentary
Antimalarial cocktails--tropical flavours of the month
Combining drugs to treat infections caused by mycobacteria and HIV is an
effective strategy. How well does it work against drug-resistant Plasmodium
falciparum malaria, for which artemisinin-based combinations have been
particularly strongly advocated?(1) And which combinations should be used?
Recently, two fixed-dose combinations have been brought to market:
atovaquone-proguanil(2) and artemether-lumefantrine(3), and many other
cocktails are being actively investigated.
In this issue of The Lancet, Grant Dorsey and colleagues examine three such
combinations for childhood malaria in Uganda. Healthy children were randomly
assigned one of three treatment regimens: sulfadoxine-pyrimethamine alone or
the same combination with either amodiaquine or with artesunate (an
artemisinin derivative). The children were then treated with the assigned
combination when they contracted uncomplicated malaria in the following
year. The regimen was maintained for subsequent infections, recrudescences
notwithstanding. This design has the effect of amplifying differences in
efficacy between treatment groups. Sulfadoxine-pyrimethamine combined with
amodiaquine, which is one of the cheapest combinations, gave the best
overall results when taking into account risk of recrudescence after 14
days. Sulfadoxine-pyrimethamine with amodiaquine reduced the rate of
subsequent treatments for malaria by 54% compared with
sulfadoxine-pyrimethamine monotherapy, and by 37% compared with artesunate
combined with sulfadoxine-pyrimethamine.
So should artemisinins continue to be included in antimalarial combinations?
In The Gambia, sulfadoxine-pyrimethamine combined with artesunate cured 98%
of patients compared with 97% with sulfadoxine-pyrimethamine alone at day
14, making it difficult to demonstrate the added value of artesunate because
of the pre-existing high efficacy of sulfadoxine-pyrimethamine used
alone.(4) Results with one combination partner for artemisinin may also be
difficult to generalise to another. When efficacy against recrudescent
infections guides choices, an artemisinin derivative is not a consistently
advantageous addition. In Kenya, for example, artesunate increased cure
rates to only 70% when given with amodiaquine (an antimalarial with a long
half-life), which used by itself cured 41% of children 28 days after their
episode of uncomplicated malaria. In S�n�gal, artesunate failed to increase
efficacy at all when combined with amodiaquine (82% vs 81%), whereas in
Gabon the combination did improve efficacy (from 77% to 89%).(5)
There may be other reasons to include an artemisinin in antimalarial
cocktails. Patients feel better more quickly, and parasitaemia disappears
faster when artesunate (or indeed another rapidly acting antimalarial) is
included in combination with a slower-acting antimalarial. Artemisinins may
also decrease transmissibility of P falciparum. But in areas with high
transmission of malarial parasites, as in tropical Africa, this advantage
over other antimalarials could fade because rapidly reinfected individuals
will continue to maintain a pool of transmissible parasites. Furthermore, 3
days of treatment with artesunate does not completely block maturation of
immature gametocytes and their infectivity to mosquitoes.(6) Another
suggestion is that artemisinins slow down the emergence of resistance
because they have relatively short elimination half-times as well as having
plasma concentrations well above therapeutic thresholds required to kill
parasites(7) (ie, parasites that are resistant to artemisinins have not yet
been identified). However, prospective studies designed to test the idea
that resistance is slowed down are notably lacking from areas with high
malaria endemicity.
Can any general recommendations be made about antimalarial combinations from
recent studies? Whilst the theory underlying antimalarial cocktails has been
cogently argued, inconsistent results from multinational studies
(exemplified above) suggest that an artemisinin may not always be the best
ingredient. The findings of Dorsey and colleagues point to an antimalarial
combination without an artemisinin, because patients feel better more
quickly when amodiaquine is added to sulfadoxine-pyrimethamine, but also
stay better longer when compared with artesunate given with
sulfadoxine-pyrimethamine.
Large differences in the efficacy of some drugs used in monotherapy suggest
that it is difficult to generalise across Africa about ideal combination
partners. Also, both amodiaquine and sulfadoxine-pyrimethamine can cause
serious adverse reactions on rare occasions.(8-10) High-grade resistance
develops rapidly to sulfadoxine-pyrimethamine or amodiaquine in areas where
such resistance is emerging. It will therefore be of great interest to see
for how long the sulfadoxine-pyrimethamine-amodiaquine cocktail continues to
be useful. Assessment of other (including non-artemisinin-based) effective
and well-tolerated antimalarial combinations is urgently needed. Perhaps
combining two or more antimalarial drugs with short elimination half-lives
can reduce the risk of selecting for resistance more effectively.
*Peter Gottfried Kremsner, Sanjeev Krishna
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Medical Research Unit, Albert Schweitzer Hospital, Lambar�n�, Gabon;
*Department of Parasitology, Institute of Tropical Medicine, University of
T�bingen, T�bingen, Germany; and Department of Infectious Diseases, St
George's Medical School, London, UK (e-mail:peter.kremsner@uni-tuebingen.de)
References
1 White NJ. Antimalarial drug resistance and combination chemotherapy.
Philosoph Trans R Soc B 1999; 354: 739-49.
2 Radloff PD, Phillipps J, Nkeyi M, Hutchinson D, Kremsner PG. Atovaquone
and proguanil for Plasmodium falciparum malaria. Lancet 1996; 347:
1511-14.
3 von Seidlein L, Jaffar S, Pinder M, et al. Treatment of African children
with uncomplicated falciparum malaria with a new antimalarial drug, CGP
56697. J Infect Dis 1997; 176: 1113-16.
4 von Seidlein L, Milligan P, Pinder M, et al. Efficacy of artesunate plus
pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: a
double-blind, randomised, controlled trial. Lancet 2000; 355: 352-57.
5 Adjuik M, Agnamey P, Babiker A, et al. Amodiaquine-artesunate versus
amodiaquine for uncomplicated Plasmodium falciparum malaria in African
children: a randomised, multicentre trial. Lancet 2002; 359: 1365-72.
6 Targett G, Drakeley C, Jawara M, et al. Artesunate reduces but does not
prevent posttreatment transmission of Plasmodium falciparum to Anopheles
gambiae. J Infect Dis 2001; 183: 1254-59.
7 Krishna S, Planche T, Agbenyega T, et al. Bioavailability and preliminary
clinical efficacy of intrarectal artesunate in Ghanaian children with
moderate malaria. Antimicrob Agents Chemother 2001; 45: 509-16.
8 Steffen R, Fuchs E, Schildknecht J, et al. Mefloquine compared with other
malaria chemoprophylactic regimens in tourists visiting East Africa. Lancet
1993; 341: 1299-303.
9 Hatton C, Peto T, Bunch C, et al. Frequency of severe neutropenia
associated with amodiaquine prophylaxis against malaria. Lancet 1986; 1:
411-14.
10 Sturchler D, Mittelholzer ML, Kerr L. How frequent are notified severe
cutaneous adverse reactions to Fansidar? Drug Saf 1993; 8: 160-68.
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