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Growing resistance to a common insecticide used against mosquitoes, combined with falling immunity among the population as transmission declined, appears to have triggered a rebound in the disease.
Two and a half years after the campaign successfully cut the number of cases, they have risen even higher than before the programme was launched, among adults and older children.
The finding raises doubts about the worldwide strategy, led by Bill Gates, to wipe out malaria by distributing insecticide-treated bed nets and effective drugs to the 2.5 billion people who live in high-risk areas around the globe.
The world's biggest philanthropist threw down a challenge to the global health community in 2007 to eliminate the disease in his lifetime.
Funding from all sources for malaria control soared following his intervention to more than $10 billion (£6.5 billion), a hundredfold rise in a decade.
More than 300 million bed nets have been distributed since 2000 and are estimated to have saved more than one million lives, according to the Roll Back Malaria Partnership.
The question the latest research raises is whether the strategy may do more harm than good by creating conditions for a resurgence of the disease that could turn out to be worse than before.
Critics of the study rejected this suggestion yesterday, saying malaria varied widely from one year to the next and the research was conducted over too short a time period and in too small an area to draw safe conclusions.
When in 2008, insecticide-treated bed nets were distributed in Dielmo, Senegal, situated on malaria-infested marshland beside a stream, the incidence of the disease fell sharply and remained low for two years.
But between September and December 2010, two and a half years later, cases rose to even higher levels than previously in adults and older children.
Researchers found that 37 per cent of Anopheles gambiae mosquitoes – the species responsible for half of Africa's malaria cases – were resistant to the insecticide deltamethrin, recommended by the World Health Organisation to treat bed nets.
The genetic mutation responsible for conferring resistance in the insects increased from 8 per cent in 2007 to 48 per cent in 2010.
Jean-Francois Trape of the Institut de Recherche pour le Developpement in Dakar, Senegal, and colleagues who led the study published in The Lancet, said: "These findings are of great concern since they support the idea that present methods and policies will not sustain – at least in older children and adults – a substantial decrease in malaria morbidity in many parts of Africa where Anopheles gambiae is the major vector and acquired clinical immunity is a key epidemiological factor. Strategies to address the problem of insecticide resistance and to mitigate its effects must be urgently defined and implemented."
The world has been striving to eliminate the disease for more than 50 years and it is not the first time doubts have been raised about the best way forward.
The task is immense. In 2008, it killed 863,000 people. Almost 90 per cent were in Africa and of those, almost 90 per cent were children under five.
Africa's leaders signed a declaration in Abuja, Nigeria, in 2000 to "halve the malaria mortality for Africa's people by 2010". Initially progress was slow but since 2007 dramatic progress has been made thanks to the huge rise in bed nets and artemesinin based drugs.
Malaria cases and deaths have been reduced by up to 80 per cent in 10 African countries since 2000, including Ethiopia, Ghana, Rwanda, Zambia and Zanzibar. In coastal Kenya, cases of severe malaria among children fell 90 per cent in five years.
The question that divides experts is what penalties may follow this success.
The usual pattern for youngsters in central Africa, near the equator where malaria is concentrated, is to suffer repeated infections through childhood which, provided they survive them, gradually build up their immunity.
Once they are beyond the age of five they have a level of natural protection. As adults they may continue to suffer regular bouts of fever but often no worse than a Western dose of flu.
But once malaria is controlled in a community and a generation of children has grown up with no immunity to the disease, the impact of an outbreak could be severe. Some experts argue that a low level of malaria is good - to maintain immunity in the population.
Dr Drape and his collegues note that in Zambia, Rwanda and the island of Sao Tome - countries where cases and deaths have been successfully reduced by the introduction of bed nets and other measures - there has subsequently been a rise in the disease.
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