[e-drug] Rescuing malaria treatment, or not?

["E-Drug" <e-drug@healthnet.org>]

E-DRUG: Rescuing malaria treatment, or not?
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[thanks to Andy Gray for spotting this. He added: "This week's Lancet has a challenging pair of articles - a paper from Uganda on the efficacy of various combinations for malaria and a commentary from Attaran. Partly their conflict revolves around notions of efficacy and effectiveness". Below first the original article, then the comments by Attaran. WB]
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http://www.thelancet.com/journal/vol364/iss9449/full/llan.364.9449.primary_research.31328.1 

Combination treatments for uncomplicated falciparum malaria in Kampala, Uganda: randomised clinical trial  

Sarah G Staedke, Arthur Mpimbaza, Moses R Kamya, Bridget K Nzarubara, Grant Dorsey, Philip J Rosenthal 

Lancet 2004; 364: 1950-57 
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Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA, USA (S G Staedke MD, G Dorsey MD, P J Rosenthal MD); and Makerere University Medical School, Kampala, Uganda (A Mpimbaza MBChB, M R Kamya MMed, B K Nzarubara MBChB) 
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Correspondence to: Dr Philip J Rosenthal, Department of Medicine, University of California San Francisco, Box 0811, San Francisco, CA 94143, USA rosnthl@itsa.ucsf.edu

Summary 

Background Plasmodium falciparum resistance has rendered chloroquine monotherapy ineffective in much of Africa, but data on alternative regimens are limited. We compared chloroquine+sulfadoxine-pyrimethamine, amodiaquine+sulfadoxine-pyrimethamine, and amodiaquine+artesunate for treatment of uncomplicated malaria in Kampala, Uganda. 

Methods Of 1017 consecutive patients aged 6 months to 10 years with uncomplicated malaria who were screened, 418 were randomised to receive: chloroquine (25 mg/kg over 3 days) and sulfadoxine-pyrimethamine (25 mg/kg sulfadoxine, 1725 mg/kg pyrimethamine, single dose); amodiaquine (25 mg/kg over 3 days) and sulfadoxine-pyrimethamine; or amodiaquine and artesunate (4 mg/kg daily for 3 days). Primary efficacy outcomes were 28-day clinical failure risks, adjusted and unadjusted by genotyping to distinguish new infection and recrudescence. The primary safety endpoint was incidence of serious adverse events during follow-up. Analysis was intention to treat and per protocol. 

Findings 18 patients were excluded before enrolment. Of those enrolled, 384 of 400 (96%) were assigned an efficacy outcome and 396 (99%) were assessed for safety. Risk of 28-day clinical treatment failure was significantly higher with chloroquine+sulfadoxine-pyrimethamine (44/125 [35%]) than with amodiaquine+sulfadoxine-pyrimethamine (12/129 [9%]; risk difference 26% [95% CI 16-36]; p<070001) or amodiaquine+artesunate (3/130 [2%]; 33% [24-42]; p<070001). The greater risk of clinical treatment failure with amodiaquine+sulfadoxine-pyrimethamine was balanced by a lower risk of new infection, resulting in a similar need for retreatment over 28 days for amodiaquine+sulfadoxine-pyrimethamine (17/129 [13%]) and amodiaquine+artesunate (16/130 [12%]; p=07854). Serious adverse events were uncommon with all regimens. 

Interpretation Risk of treatment failure with chloroquine+sulfadoxine-pyrimethamine was unacceptably high. Combinations of amodiaquine and sulfadoxine-pyrimethamine or artesunate were significantly more efficacious, and each regimen could be an appropriate alternative for treatment of uncomplicated malaria in Africa. 

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http://www.thelancet.com/journal/vol364/iss9449/full/llan.364.9449.analysis_and_interpretation.31370.1 

Rescuing malaria treatment, or not?  

In this week's Lancet, Sarah Staedke and colleagues' paper, while technically excellent, echoes some fallacies in how people think of treatment of malaria. These researchers report on the treatment efficacy of different antimalarial combination therapies in Uganda. They compared the familiar, but outdated, chloroquine plus sulfadoxine-pyrimethamine with the much more effective combinations of amodiaquine and sulfadoxine-pyrimethamine, or amodiaquine and artesunate. 

Staedke and colleagues asked which of the last two combination therapies would be most effective in Uganda--is amodiaquine, being common to both, best combined with sulfadoxine-pyrimethamine or with artesunate? Their conclusion is remarkably bold: both therapies are equally acceptable, because although amodiaquine and artesunate was best at treating the patient (98% success), amodiaquine and sulfadoxine-pyrimethamine was only somewhat inferior (91% treatment success, p=07018), and it has the fortuitous side-effect of protecting against future malarial infections. Over the 28-day follow-up, patients given either therapy sought another treatment, or "rescue therapy" as Staedke calls it, about equally often, although usually for different reasons. Patients on amodiaquine and sulfadoxine-pyrimethamine needed retreatment because the combination therapy failed to treat their malaria the first time, while patients on amodiaquine and artesunate needed a second treatment (but not retreatment) because they got a second malarial infection. 

These data indicate a difference in the rate of treatment failure, which Staedke and colleagues overlook, arguing instead that the frequency of "rescue therapy provides a more meaningful public-health indicator". Since the 450% greater risk of clinical treatment failure with amodiaquine and sulfadoxine-pyrimethamine was "balanced" by a lower risk of new infection within 28 days, the researchers conclude that either combination will work in Uganda. 

Staedke and colleagues' emphasis on rescue therapy is unpersuasive. To state quantitatively that a higher risk of treatment failure can be balanced by a lower risk of new infection is to enter into a qualitatively illogical comparison. A treatment failure means that a sick patient gets sicker--possibly until he or she is dead. A new infection means that the patient returns to clinic for treatment--certainly a bother. Death and bother are highly different. They never balance. 

The purpose of a good first-line therapy is to treat uncomplicated malaria. Treatment failure is undesirable because it can lead to severe and complicated malaria, including renal failure, hepatic failure, respiratory distress, shock, low birthweight, coma, or death.1 Making treatment failure into a euphemism by incorporating it within the definition of rescue therapy not only lowers the standard of care, but probably wastes money too. Malaria that advances through mild, moderate, and severe clinical stages typically costs 4-5-fold more to manage at each worsening turn.2,3 In the long term, there are also losses in human capital, such as brain-damaged children who survive cerebral malaria.4 Although health economists cannot determine the exact costs, statistical models show that quasi-effective medicines such as amodiaquine and sulfadoxine-pyrimethamine are often poor value.5 Their useful therapeutic life, before succumbing to resistance, is also short.6 

Current events have also left most of Staedke and colleagues' recommendations behind. Uganda and the East African Network for Monitoring Antimalarial Therapy in 2003 found that amodiaquine and sulfadoxine-pyrimethamine treatment fails at a rate of up to 62% by the 28th day.7 These data led Uganda to change its treatment policy in 2004 to the fixed-dose combination of artemether and lumefantrine, which the government is now implementing.8 

Uganda's change is proof that malaria-endemic countries can generate useful data to orient their health policies. Importantly, the change is made financially possible by the Global Fund to Fight Aids, Tuberculosis and Malaria, which has undergone a nimble policy change of its own. After I and others documented how the Global Fund financed ineffective medicines for malaria that contributed to child mortality--a view the Global Fund initially rejected as "factually incorrect, in just about every respect"--the Fund then executed an about-face.9,10 Pressure from journalists and the US Senate persuaded it to create an unprecedented US$200-million escrow account to purchase artemisinin combination therapies, such as the one Uganda chose.11 With money finally promised, more countries adopted artemisinin-combination therapy in the first 6 months of 2004 than in all years before, making this the largest revolution in treatment policy for malaria in the six decades since chloroquine. 

The implications of these changes are vast. Rather than clinical efficacy trials, more urgently needed are clinical studies of the effectiveness of artemisinin-combination therapies in African field conditions, to monitor the success (or failure) of the implementation process. Also needed is pressure on the UK Department for International Development, the US Agency for International Development, and the World Bank, which purchase little, if any, artemisinin-combination therapy. The Senate and the General Accounting Office in the USA are now investigating USAID's inaction, and other donors should expect similar probes unless they act proactively.12 Much has been achieved in 2004; neither science nor policy can afford to let up. 

Amir Attaran 

Institute of Population Health and Faculty of Law, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5 

aattaran@riia.org 

I have in the past advised Novartis on its not-for-profit partnership with WHO for the joint distribution of artemisinin-based combination therapy, and advised or been a consultant to WHO and Midecins Sans Frontihres. 

1 Murphy SC, Breman JG. Gaps in the childhood malaria burden in Africa: cerebral malaria, neurological sequelae, anemia, respiratory distress, hypoglycemia, and complications of pregnancy.  Am J Trop Med Hyg  2001; 64 :(suppl 1-2) 57-67. 
2 Bloland P, Colmenares J, Gartner G, Schwarz IK, Lobel H. Cost and appropriateness of treating Plasmodium falciparum in the United States.  J Travel Med  1995; 2: 16-21. 
3 Lwin AM, Umenai T. Cost analysis of malaria patients in Taikkyi Township Myanmar.  Asia Pac J Public Health  1999; 11: 94-100. 
4 Brewster DR, Kwiatkowski D, White NJ. Neurological sequelae of cerebral malaria in children.  Lancet  1990; 336: 1039-43. 
5 Goodman CA, Coleman PG, Mills AJ. Changing the first line drug for malaria treatment: cost-effectiveness analysis with highly uncertain inter-temporal trade-offs.  Health Econ  2001; 10: 731-49. 
6 Watkins WM, Sibley CH, Hastings IM. The search for effective and sustainable treatments for Plasmodium falciparum malaria in Africa. Am J Trop Med Hyg 2004 (in press). 
7 East African Network for Monitoring Antimalarial Treatment. Aug 16, 2004: http://www.eanmat.org/default.asp?strPage=DownloadData (accessed Nov 1, 2004). 
8 Reprogramming malaria grants for rounds 1-3: a consultation at GFATM, Geneva, 02 May 2004. Report of meeting convened by The Global Fund to Fight AIDS, Tuberculosis and Malaria. Geneva, Switzerland, May 2, 2004 (available from AA). 
9 Attaran A, Barnes KI, Curtis C, et al. WHO, the Global Fund, and medical malpractice in malaria treatment.  Lancet  2004; 363: 237-40.
10 Agence France-Presse. WHO, Global Fund fight back in row over malaria drug policy. Jan 17, 2004. 
11 Letter to Country Coordinating Mechanisms from Brad Herbert (The Global Fund to Fight AIDS, Tuberculosis and Malaria) and Dr Awa Marie Coll-Seck (Roll Back Malaria Partnership), Aug 26, 2004 (available from AA). 
12 Carter T. Use of DDT urged in malaria fight. Washington Times Sept 16, 2004.