Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study
BMJ 2004; 328 doi: https://doi.org/10.1136/bmj.37977.653750.EE (Published 04 March 2004) Cite this as: BMJ 2004;328:545All rapid responses
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Dear Sir,
In his letter of 1 April 2004, Professor NJ White characterizes
sulfadoxine-pyrimethamine (SP) as ineffective in Malawi and refers to the
proportion of persons with no parasites 28 days after SP treatment of
uncomplicated falciparum malaria as a “cure rate”. How is the reader to
reconcile our article’s report of a sustained 80% efficacy1 with Professor
White’s assertion that we found sustained cure rates of less than 40%?
We reported our results using the standard definition of antimalarial
therapeutic efficacy in high transmission areas, which is based on follow-
up through 14 days after treatment.2 If this is a “blinkered assessment”
it was blinkered by expert consensus and widely used and accepted as the
standard definition until less than one year ago, after the study we
reported was concluded. We also reported parasitaemia prevalences at 28
days after treatment, but these data do not provide cure rates in any
accepted or standard sense, particularly since our study did not
distinguish between reinfections and recrudescences. In high transmission
settings, the proportion of persons with malaria infections increases over
time following a treatment episode, so the “cure rate” declines as the
definition of efficacy is extended from 14 days to 28 days or longer. Not
surprisingly, even lower “cure rates” for drugs (including artemisinin-
based combination therapy) are found when follow-up is extended beyond 28
days, even after genotyping to correct for reinfections.3 Which measure of
drug efficacy – adequate clinical response or complete eradication of the
initial parasite population by 28 days – more accurately predicts a drug’s
usefulness in the long term against the important endpoints in a
community, namely severe disease and mortality? Actual data are lacking by
which to answer this question.
White argues that severe and fatal disease are a consequence of
absence of specific immunity to a new parasite, and that the drug used for
treatment is therefore the principal determinant of the outcome. These are
plausible suggestions, but they would be greatly strengthened if supported
by data acquired in a high-transmission setting.
A longitudinal study compared the efficacy of SP and chlorproguanil-
dapsone over time in Malawi from 1997 to 1999.4 This study used a non-
standard definition of efficacy, but it was conducted in the same clinic
at the same time as our study, and found that SP had an efficacy rate of
80%, in close agreement with our contemporaneous standard measure of SP
efficacy. Chlorproguanil-dapsone, a short-acting antifolate combination,
had 95% efficacy. In Malawi, children treated with SP for all episodes of
malaria over the course of a year had no more episodes of uncomplicated
malaria, anemia or severe malaria than those treated for all malaria
episodes with chlorproguanil-dapsone, despite the latter’s much higher
efficacy. The benefit of chlorproguanil-dapsone’s higher efficacy was
effectively cancelled out by the prolonged prophylactic effect of the
longer acting but less efficacious SP. Radical cure, which can be achieved
with short-acting, highly efficacious combinations, should be the goal in
low transmission settings where the risk of reinfection is low, but this
study demonstrates that over time, children in areas of high transmission
may do as well or better with a longer acting drug with mediocre efficacy
than with a short acting regimen with high efficacy.
In addition to efficacy, factors including epidemiology,
pharmacokinetics, pharmacodynamics, compliance, and economic
considerations must all be taken into account in assessing the benefit of
antimalarial treatment regimens. Large longitudinal studies are required
to demonstrate a benefit of more complex first-line drug regimens against
the end-points that matter most – severe malaria and child mortality.
Assumptions that the best approach to malaria therapy in one setting can
be extrapolated, in the absence of data, to all other settings, are
unwise.
Nevertheless, we share the concerns expressed by Professor White and
Dr. Pascal Ringwald and agree with the editorial by Professor Brian
Greenwood that the observed degree of efficacy (however it is defined)
reported in our study is less than satisfactory. Hence the statement in
our paper that the efficacy levels we reported for SP ‘do not warrant
complacency about seeking alternative treatments for its replacement’. (We
are currently working with the national programme to identify the best
alternatives for Malawi). Of particular concern is the risk of anemia and
recurrent clinical episodes that comes with impaired treatment efficacy,
as noted by Dr. Ringwald. In low transmission settings, highly curative
treatment regimens are clearly better than treatments with impaired
efficacy. In Africa, however, the health benefit of treatment regimens is
not solely a function of curative efficacy.
Professor White ends his letter by blaming the use of SP for
increases in malaria-attributable morbidity and mortality in Eastern and
Southern Africa between 1990 and 1998. Malawi introduced SP as the first
line antimalarial in 1993. This was accompanied by a 20% reduction in
infant mortality and a 22% reduction in child mortality from 1990 through
2000,5 despite increasing rates of HIV mortality during this period, and
in contrast to increasing infant and child mortality in the rest of the
region, where other countries continued to use chloroquine. It is likely
that the continued use of chloroquine in the face of truly dismal efficacy
rates, while waiting for long delayed alternative treatments, was
responsible for higher mortality among children in other countries of this
region. It may indeed be too late now for other countries to enjoy the
benefit from switching to SP that Malawi did, but it seems likely that had
these countries joined Malawi in this switch in 1993, large numbers of
children’s lives would have been saved. The situation is changing, and all
countries must now seek to introduce optimal first-line treatments and to
monitor their effectiveness against malaria-attributable mortality in
children.
References
1. Plowe CV, Kublin JG, Dzinjalamala FK, Kamwendo DS, Mukadam RA,
Chimpeni P et al. Sustained clinical efficacy of sulfadoxine-pyrimethamine
for uncomplicated falciparum malaria in Malawi after 10 years as first
line treatment: five year prospective study. BMJ 2004.
2. WHO. Assessment of therapeutic efficacy of antimalarial drugs for
uncomplicated Falciparum malaria in areas with intense transmission. 1996.
Geneva, World Health Organization, Division of Control of Tropical
Diseases.
3. Dorsey G, Njama D, Kamya MR, Cattamanchi A, Kyabayinze D, Staedke
SG et al. Sulfadoxine/pyrimethamine alone or with amodiaquine or
artesunate for treatment of uncomplicated malaria: a longitudinal
randomised trial. Lancet 2002;360:2031-8.
4. Sulo J, Chimpeni P, Hatcher J, Kublin JG, Plowe CV, Molyneux ME
et al. Chlorproguanil-dapsone versus sulfadoxine-pyrimethamine for
sequential episodes of uncomplicated falciparum malaria in Kenya and
Malawi: a randomised clinical trial. Lancet 2002;360:1136-43.
5. Millenium Indicators Database.
http://unstats.un.org/unsd/mi/mi_goals.asp. Statistics Division, World
Health Organization, Geneva.
Competing interests:
None declared
Competing interests: No competing interests
Editor,
Plowe et al(1)validate anecdotal reports which have suggested that
Sulfadoxine-pyrimethamine is still efficacious in Malawi despite
considerable evidence that suggests otherwise.(2,3)
How long this efficacy would last can only be left to speculation.
They are correct in stating that regional studies on drug efficacy
and not predictions based on experiences in very different epidemiological
settings should form the basis of rational antimalarial drug policy.(1)
This is evident from the differing levels of Chloroquine(CQ) and
Sulfadoxine-pyrimethamine(SP) resistance seen in East Africa when compared
to West Africa.
However I disagree with the statement that "countries still using CQ
despite high resistance, but where SP remains efficacious should consider
switching to SP as an interim drug while waiting for more effective
combination therapies."
This statement should be interpreted with caution,because for a West
African country such as Nigeria, SP and CQ resistance has been reported
over a decade ago.(4-6)
However, both drugs still demonstrate varying degrees of efficacy even in
the face of perennial transmission of malaria and drug pressure.(7)
A policy shift to SP monotherapy as first line now would only result in
the squandering of limited resources for health,because in a few years
time there may be a need to change policy again.
Combination therapy is the logical and urgent alternative to help
reduce malaria incidence,prevent the emergence of drug resistance and
possibly extend the useful therapeutic life of standard
antimalarials.(including SP)(8)
However the cost implications of implementing the available Artesunate
Combination Therapies(ACT)is daunting for most countries in sub-saharan
Africa.
A recent meta-analysis showed that 3 days artesunate combined with
standard antimalarials reduced treatment failures in Africa.(9)
This positive effect was especially noticeable with SP,
other antimalarial drug combinations have also been found to be effective
and much cheaper than ACT's. Amodiaquine-Sulfadoxine-pyrimethamine was
superior to Artesunate-Sulfadoxine -pyrimethamine for preventing late
recrudescent infections in Uganda.(10)
I would argue that these alternative combination therapies e.g
(Amodiaquine/SP)may prove the best candidates as "short term strategy"
until cheaper ACT's with proven safety in pregnancy are available, not
Sulfadoxine-pyrimethamine monotherapy.
AT Abegunde
References
1. Plowe CV, Kublin JG, Dzinjalamala FK et al. Sustained efficacy of
sulfadoxine -pyrimethamine for uncomplicated malaria in Malawi after
10years as first line treatment:Five year prospective study. BMJ
2004;328(7439):545
2.Verhoeff FH, Brabin BJ, Masache P et al. Parasitological and
haematological responses to treatment of Plasmodium falciparum with
Sulfadoxine-pyrimethamine in southern Malawi. Ann.Trop.Med.Parasitol.
1997;91:133-40
3.Nwanyanwu OC,Ziba C, Macheso A et al. Efficacy of Sulfadoxine-
pyrimethamine for acute uncomplicated malaria in Malawian children under
five years old. Trop. Med.Int.Health 2000;5:355-8
4.Lege-oguntoye L,Adagu SI, Werblinska B et al. Resistance of
Plasmodium Falciparum to sulfadoxine -pyrimethamine combination in semi-
immune children in Zaria,northern Nigeria. Trans.R.Soc.Trop.Med.Hyg
1990;84(4): 505-6
5.Adagu SI, Okoyeh JN, Lege-Oguntoye L et al. Efficacy of a 3 day
oral regimen of Quinine in an area of northern Nigeria with low grade
resistance of Plasmodium falciparum to Chloroquine and Sulfadoxine-
pyrimethamine.J.Trop.Med.Hyg 1995;98(5):296-8
6. Happi CT,Gbotosho GO, Sowunmi A et al. Molecular analysis of
Plasmodium Falciparum recrudescent malaria infections in children treated
with Choroquine in Nigeria. Am.J.Trop.Med.Hyg 2004;70(1): 20-6
7.Sowunmi A, Fehintola FA, Adedeji AA et al. Comparative efficacy of
Chloroquine plus chlorpheniramine alone and in sequential combination with
sulfadoxine-pyrimethamine for the treatment of acute uncomplicated
falciparum malaria in children. Ann.Trop.Med.Parasitol. 2000;94(3):209-17
8.Nosten F, Brasseur P.Combination therapy for malaria: The way
foward. Drugs 2002;62:1315-29
9.Adjiuk M,Babiker A,Garner P et al;International Artemisinnin study
group.Artesunate combinations for the treatment of malaria:A meta-
analysis. Lancet 2004;363(9402):9-17
10.Dorsey G, Njama D, Kamya MR et al. Sulfadoxine-pyrimethamine alone
or with Amodiaquine or Artesunate for the treatment of uncomplicated
malaria: A longitudinal randomised controlled trial.Lancet 2002;360:2031-
38
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir
I wonder if the article by Plowe et al (BMJ 6 March 328; 545-8) 1 might
not be better titled “Sustained lack of efficacy of sulfadoxine-
pyrimethamine for uncomplicated falciparum malaria in Malawi after 10
years as first line treatment; five year prospective study”. As the
authors and others 1,2 have documented, by the start of the study period
five years ago Plasmodium falciparum in Malawi had already acquired
significant resistance to SP; parasites with quintuple mutations in the
genes encoding the drug targets (3 mutations in Pfdhfr and 2 in Pfdhps)
were already widely prevalent. Infections with such parasites in non-
immune patients are associated with high failure rates. This explains the
sustained lack of efficacy in Malawi documented carefully, in large
numbers of patients in this report; cure rates in children with acute
falciparum malaria assessed at 28 days remained steadily less than 40%
over the five year study period. This is confirmed by the Malawi component
of the recent WHO-TDR multicentre evaluation of artemisinin combination
treatment (with some authors common to both reports); the cure rate
assessed 28 days following observed administration of SP was only 23%3,
and this for one of the major killing diseases of childhood. A 77 %
failure rate is amongst the worst SP responses ever documented! Only 7%
(5/71) of reported trials on SP have had failure rates worse than this4.
Reinfection was not a major confounder; the PCR genotyping corrected 28
day cure rate was 32%.
Before SP was introduced widely it was very effective in Malawi5 , but,
since then, efficacy has fallen dramatically1,3,6-9 (Table). The front
page of the BMJ was wrong; SP is not “still working”. A drug giving a cure
rate of consistently less than 40% for a potentially life-threatening
infection cannot be described as having “good efficacy”. Particularly when
highly effective alternatives exist. Can you imagine endorsing an
antibiotic with a more than 60% failure rate for use in European or
American children with those words? These figures reflect dangerously poor
efficacy. It is the immune response which is “still working”. In Malawi,
where children may receive an infection each week or even more frequently,
there is clearly intense exposure to malaria, and immunity is gained in
early childhood. But malaria is still a major cause of childhood death.
Children die from malaria because they do not have sufficient immunity to
the particular parasite causing their infection, and because they do not
receive effective treatment. They may well have immunity to many other
parasites, and, as severe malaria occurs in only a small minority of
infections, the majority of infections are controlled by the host’s
defences10. Treatment responses appear to be satisfactory for ineffective
drugs, particularly with the blinkered assessment provided by the blunt
tool of “clinical response” assessed at 14 days. But demographic
surveillance system data from Eastern and Southern Africa suggest that
malaria attributable mortality in children almost doubled between 1990 and
1998, whereas by contrast non-malaria related mortality fell. The use of
ineffective drugs, such as SP in Malawi, may well be to blame11.
Professor NJ White
Faculty of Tropical Medicine,
Mahidol University,
420/6 Rajvithi Rd,
Bangkok 10400,
Thailand
E mail: nickw@tropmedres.ac
http://www.tropmedres.ac
Table Declining therapeutic responses to sulphadoxine –pyrimethamine in Malawian children with acute falciparum malaria; 1987 -2003 Author Day 7 assessment Day 14 assessment Day 21 or Day 28 assessment of cure Heymann D et al 19875 100% 100% (D21) Nwanyanwu et al 19966 98% 98% Verhoeff et al 19977 98% 90.5% Nwanyanwu et al 20008 89% 81-93% MacArthur et al 20009 80% WHO –TDR study 2000-23 53% 23%* (D28) Plowe et al 20041 78-88% 61-73% 27-39% (D28) * The true success rate, confirmed with PCR genotyping was 36/113; 32%
References
1. Plowe CV, Kublin JG, Dzinjalamala FK, Kamwendo DS, Mukadam RA,
Chimpeni P, Molyneux ME, Taylor TE. Sustained clinical efficacy of
sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi
after 10 years as first line treatment: five year prospective study. BMJ.
2004 ;328:545-8.
2. Bwijo B, Kaneko A, Takechi M, Zungu IL, Moriyama Y, Lum JK,
Tsukahara T, Mita T, Takahashi N, Bergqvist Y, Bjorkman A, Kobayakawa T.
High prevalence of quintuple mutant dhps/dhfr genes in Plasmodium
falciparum infections seven years after introduction of sulfadoxine and
pyrimethamine as first line treatment in Malawi.
Acta Trop. 2003; 85: 363-73.
3. Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N;
International Artemisinin Study Group. Artesunate combinations for
treatment of malaria: meta-analysis. Lancet. 2004; 363: 9-17.
4. Myint HY, Tipmanee P, Nosten F, Pukrittayakamee S, Day NPJ,
Looareesuwan S, White NJ. A systematic overview of published antimalarial
drug trials. Trans R Soc Trop Med Hyg; 2004, 98: 73-81.
5. Heymann DL, Khoromana CO, Wirima JJ, Campbell CC. Comparative
efficacy of alternative primary therapies for Plasmodium falciparum
infections in Malawi. Trans R Soc Trop Med Hyg. 1987; 81: 722-4.
6. Nwanyanwu OC, Ziba C, Kazembe P, Chitsulo L, Wirima JJ, Kumwenda
N, Redd SC.Efficacy of sulphadoxine/pyrimethamine for Plasmodium
falciparum malaria in Malawian children under five years of age. Trop Med
Int Health. 1996;1: 231-5.
7. Verhoeff FH, Brabin BJ, Masache P, Kachale B, Kazembe P, Van der
Kaay HJ. Parasitological and haematological responses to treatment of
Plasmodium falciparum malaria with sulphadoxine-pyrimethamine in southern
Malawi. Ann Trop Med Parasitol. 1997; 91: 133-40.
8. Nwanyanwu OC, Ziba C, MacHeso A, Kazembe P. Efficacy of
sulphadoxine-pyrimethamine for acute uncomplicated malaria due to
Plasmodium falciparum in Malawian children under five years old. Trop Med
Int Health. 2000; 5: 355-8.
9.MacArthur J, Stennies GM, Macheso A, Kolczak MS, Green MD, Ali D,
Barat LM, Kazembe PN, Ruebush TK 2nd.Efficacy of mefloquine and
sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium
falciparum infection in Machinga District, Malawi, 1998. Am J Trop Med
Hyg. 2001; 65: 679-84.
10. Bull PC, Lowe BS, Kortok M, Molyneux CS, Newbold CI, Marsh K.
Parasite antigens on the infected red cell surface are targets for
naturally acquired immunity to malaria. Nat Med. 1998;4: 358-60.
11. Korenromp EL, Williams BG, Gouws E, Dye C, Snow RW. Measurement
of trends in childhood malaria mortality in Africa: an assessment of
progress toward targets based on verbal autopsy. Lancet Infect Dis. 2003;
3: 349-358.
Competing interests:
None declared
Competing interests: TableDeclining therapeutic responses to sulphadoxine –pyrimethamine in Malawianchildren with acute falciparum malaria; 1987 -2003Author Day 7 assessment Day 14 assessment Day 21 or Day 28 assessmentof cureHeymann D et al 19875 100% 100% (D21)Nwanyanwu et al 19966 98% 98% Verhoeff et al 19977 98% 90.5% Nwanyanwu et al 20008 89% 81-93% MacArthur et al 20009 80% WHO –TDR study 2000-23 53% 23%* (D28)Plowe et al 20041 78-88% 61-73% 27-39% (D28) * The true success rate, confirmed with PCR genotyping was 36/113; 32%
Is sulfadoxine-pyrimethamine safe as a first line therapy,is the
main question here. Although it show satisfactory efficacy but what about
its side effects.As a doctor belong to the country where the rate of
malaria is also high and use of sulfadoxine-pyrimethamine is not uncommon
specially by the local GPs, i had seen many severe side effect of this
drug which is also too frequent namely the aplastic anemia and other
hematological disorder.Patient may get rid of malaria by the sulfadoxine-
pyrimethamine use but its stay in hospital usually increases and mortality
also increases because of the side effect of this drug.
I feel that use of cholorquine is still remain the first line therapy
in uncomplicated cases of falciparum malaria in adults. If you encounter
the complicated case then its better to deal it with quinine or
halofantrine.
Use of this drug as a first line therapy is not recommended and
specially in poor countries.
Competing interests:
None declared
Competing interests: No competing interests
I read with interest the article by Plowe et al. (1) on the sustained
clinical efficacy of sulfadoxine-pyrimethamine in Malawi. Studies
assessing long term trends of drug efficacy are rare, and are useful for
updating antimalarial treatment policies. Nevertheless, I would like to
add some comments on the methods applied to enhance the interpretation of
the data.
WHO has developed several standardized protocols to assess the
efficacy of antimalarial drugs. Although the outcomes were classified in
the 1973 guideline as RI-RII-RIII levels of resistance, later and current
protocols are intended to determine treatment failures and not resistance
patterns of the parasite. Treatment failure is not identical to parasite
resistance. Some treatment failures may be due to incomplete absorption or
rapid clearance of the drug; conversely treatment success can be recorded
in semi-immune adults infected with resistant parasites. Recently, WHO
published a revised standardized protocol for the assessment of
antimalarial drug efficacy, giving clear indications of outcome
classifications, the target groups to be monitored and the duration of the
follow-up according to the drug tested (2).
The new classification is appropriate for symptomatic patients, and
includes not only clinical but also parasitological criteria. Since
Adequate Clinical and Parasitological Response (ACPR), Late
Parasitological Failure (LPF), Late Clinical Failure (LCF) and Early
Treatment Failure (ETF) results are most often similar to the previous RI-
II-III classification, it becomes redundant now to classify the response
based on both classifications. But, an examination of WHO's database on
antimalarial drug efficacy has shown that LCF and LPF correspond closely
to RI, and ETF to RIII + RII, contradicting the authors' claim that ETF is
systematically overestimating the true early failure rate.
Regardless of the intensity of the malaria transmission, any evaluation
should focus on treatment efficacy in children under 5 years. Even in
populations with little acquired immunity, younger children have less
favourable therapeutic response to antimalarial drugs than do older
children and adults. Adults have been included in this survey; it would be
interesting to analyse the data focusing only on young children.
Results of the therapeutic efficacy test is only one of the factors
that can lead to the decision to change current drug policy; increased
malaria-associated morbidity and mortality may also be indicators of
failure of the existing policy. It has been clearly demonstrated that
persistent parasitaemia is associated with anaemia, increased risk of
clinical recrudescence and increased gametocyte carriage. A technical
meeting convened by WHO/AFRO in Harare, 14-15 August 2003, agreed that, in
intense transmission areas, asymptomatic parasitological failure (quoted
as LPF in the new protocol) should be an additional indicator for the
interpretation of the test. It was also agreed that an unacceptable level
of failures is reached when clinical failure at day 14 (ETF+LCF) >= 15%
and total failure (ETF+LCF+LPF) >=25% (2). The authors’ data in table 2
show that these thresholds have been reached in Ndirande since 1999.
There is clear evidence that the resistance of P. falciparum to
sulfadoxine-pyrimethamine has increased in Malawi over the last ten years.
According to Plowe et al. sulfadoxine-pyrimethamine resistance was absent
in Malawi in 1990 before the drug became the first line treatment but it
emerged, with 14 day recrudescence rates (RI, RII, RIII combined), up to
36% in 1995 and 1996 in the town of Karonga (3).The level of cumulative RI
-RII-RIII parasitological failure probably reached a peak in Ndirande in
1999. Similar failure rates with chloroquine in 6 sites in Malawi led to
policy change and the adoption in 1993 of sulfadoxine-pyrimethamine as
first line treatment (4). The authors had previously demonstrated that the
triple mutations in dhfr gene and the double mutant in dhps gene, which
are good markers of sulfadoxine and pyrimethamine resistance, are highly
prevalent in Malawi (3). It would be misleading to try to correlate the
prevalence of mutants and the results of WHO therapeutic efficacy test
using the previous 1996 outcome classification, because this test did not
consider asymptomatic parasitological failures at D14, and instead
classified them under Adequate Clinical Response.
Sulfadoxine-pyrimethamine efficacy data in Malawi is a subject of
scientific debate. Behind this debate, there is a real public health issue
of delivering fully effective drugs to the population.
1. Plowe CV, Kublin JG, Dzinjalamala FK, Kamwendo DS, Mukadam RA,
Chimpeni P, et al. Sustained clinical efficacy of sulfadoxine-
pyrimethamine for uncomplicated falciparum malaria in Malawi after 10
years as first line treatment: five year prospective study. BMJ
2004;328:545-8.
2. World Health Organization (WHO). Assessment and monitoring of
antimalarial drug efficacy for the treatment of uncomplicated falciparum
malaria. Geneva, Switzerland:WHO/HTM/RBM/2003.50.
3. Plowe CV, Cortese JF, Djimde A, Nwanyanwu OC, Watkins WM,
Winstanley PA, et al. Mutations in Plasmodium falciparum dihydrofolate
reductase and dihydropteroate synthase and epidemiologic patterns of
pyrimethamine-sulfadoxine use and resistance. J Infect Dis 1997;176:1590-
6.
4. Khoromana CO, Campbell CC, Wirima JJ, Heymann DL. In vivo efficacy
of chloroquine treatment for Plasmodium falciparum in Malawian children
under five years of age. Am J Trop Med Hyg 1986;35:465-71.
Competing interests:
None declared
Competing interests: No competing interests
SP Failure rates similar in Blantyre, Malawi and KwaZulu Natal, South Africa
Dear Sir
We read the article by Plowe et al (1) (BMJ 6 March 2004, 328: 545-8)
with interest as ongoing monitoring of the therapeutic efficacy of drugs
included in a national malaria treatment policy is essential for ensuring
optimal patient management. However, we are surprised that these authors
interpret their findings as sustained clinical efficacy of sulfadoxine-
pyrimethamine (SP). The extremely high levels of parasitological failure
reported confirm that acquired immunity (and antipyretic use) is a more
important determinant of the resolution of clinical signs of malaria (most
commonly fever) than SP treatment. Thus, Plasmodium falciparum infection
in Malawi in non-immunes (such as infants or travellers) would be
associated with high treatment failure rates, and high mortality if there
is no ready access to more effective drugs.
The authors compare their findings with those we reported in KwaZulu
Natal, South Africa(2), and suggest that SP resistance arose more quickly
in KwaZulu Natal, where transmission intensity and thus immunity are lower
than in Malawi. However, the apparent “longer useful therapeutic life” of
SP reported in Malawi reflects differences in methodology and
interpretation, rather than the impact of variable transmission intensity.
In 2001 we reported a parasitological failure rate following SP
treatment of 88% after 42 days of follow up. The longer period of follow
up is necessary to capture all recrudescences (given the long elimination
half-life of SP). We reanalysed our data from 2000 (12 years after SP
implementation) at day 14 and day 28, using internationally standardised
methods for assessing antimalarial drug efficacy (3), to allow comparison
with the findings of Plowe et al in Malawi (10 years after SP
implementation). In KwaZulu Natal, intention to treat analysis of 129
patients recruited showed that the SP parasitological failure rate
observed by day 14 was 45% (95% Confidence Interval: 36 – 54%), compared
with 38% in Malawi. After 28 days of follow up, the parasitological
failure rate was 81% (95% Confidence Intervals 72 - 89%), compared with
73% in Malawi. Potentially lethal high grade treatment failures (R3
response) occurred in between 10 and 15% of patients over the five year
Malawi study, compared with 8.5% in KwaZulu Natal. This comparison of the
therapeutic efficacy of SP in Malawi and KwaZulu Natal ten and twelve
years after implementation, respectively, suggests that SP resistance had
progressed to a similarly high level after a decade in Malawi, despite the
higher intensity of malaria transmission.
The interpretation of the failure rates differs considerably between
Malawi and KwaZulu Natal. Plowe et al report that the observed levels of
treatment failure “may before long fall to unacceptable levels”. In marked
contrast, similar very high failure rates in KwaZulu Natal were considered
so serious that SP was replaced with an artemisinin-based combination,
artemether-lumefantrine within 6 months (4). Plowe et al’s advice on the
interim utility of sulfadoxine-pyrimethamine in African countries awaiting
implementation of combination antimalarial treatment, is potentially
misleading as this is not supported by their data, and as existing data,
including that from Malawi, suggest that full implementation of a malaria
treatment policy change usually takes at least 18-24 months(5).
Karen I Barnes
University of Cape Town Division of Pharmacology, South Africa
Brian L Sharp
Medical Research Council Malaria Lead Programme, South Africa
David N Durrheim
School of Public Health and Tropical Medicine, James Cook University,
Australia
1. Plowe CV, Kublin JG, Dzinjalamala FK, Kamwendo DS, Mukadam RAG,
Chimpeni P, Molyneux ME, Taylor TE. Sustained clinical efficacy of
sulfadoxine-pyrimathamine for uncomplicated falciparum malaria after 10
years as first line treatment: five year prospective study. Brit Med J
2004; 328: 545-8.
2. Bredenkamp BL, Sharp BL, Mthembu SD, Durrheim DN, Barnes KI.
Failure of sulfadoxine-pyrimathamine in treating Plasmodium falciparum
malaria in KwaZulu Natal. S Afr Med J 2001; 91: 970-2.
3. World Health Organisation (WHO). Assessment and monitoring of
antimalarial drug efficacy for the treatment of uncomplicated falciparum
malaria. Geneva, Switzerland: WHO/HTM/RBM/2003.50.
4. Baker L, Barnes K. New antimalarials treatment for KwaZulu Natal.
S Afr Med J 2001; 91(5): 358-9.
5. Bloland PB and Ettling M. Making malaria-treatment policy in the
face of drug resistance. Ann Trop Med Parasitol 1999; 93: 5-23.
Competing interests:
None declared
Competing interests: No competing interests