Effectiveness of bi-treated long lasting insecticidal nets and deployment strategy for control of malaria transmitted by pyrethroid resistant vectors

The massive scale up of long-lasting insecticidal nets (LN) from 2% in 2000 to 55% in 2015 has made the major contribution to the decline of malaria in Africa. LN effectiveness is entirely dependent on the pyrethroids, and with high LN coverage resistance has increased in distribution and strength. Leading LN brands are giving less protection than before and in North West Tanzania are failing to control malaria despite high coverage and usage rates. This problem was anticipated, and WHO has long encouraged industry to develop new types of 'combination' LN treated with new chemical compounds to overcome resistance and restore effectiveness. The strongest resistance is mediated by cytochrome P450s, enzymes that metabolise the pyrethroid to inactive compounds. One solution is the synergist PBO which inhibits the P450 system in insects. LN products combining pyrethroid and PBO are available but due to limited evidence of additional impact against malaria these nets have not been widely deployed. This situation is changing as we showed in a randomised controlled trial in Tanzania that LN with PBO (Olyset Plus) was able to control malaria transmission where standard LN failed due to resistance. Presently there are two types of PBO-LN available that differ in distribution of PBO on the net and it is not clear how they would compare making it difficult for malaria control agencies to make an informed choice. 'Mosaic LN' restrict the PBO to the roof panel where mosquitoes may first contact the net due to convection of CO2 from the sleeper inside. Others like Olyset Plus have all panels treated with PBO. Bi-treated nets incorporating new types of insecticide have also become available. A leading product mixes pyrethroid with an insect growth regulator pyriproxifen (PPF) that sterilises mosquitoes that contact the net. Another type mixes pyrethroid with the pyrrole chlorfenapyr (CFP), whose unique mode of action is unlikely to confer cross resistance with other public health insecticides. LSHTM has helped develop both types of mixture LN and has evaluated them entomologically in laboratory and experimental huts. With its in depth knowledge LSHTM is in a unique position to continue evaluation at community level for malaria control. Earlier experience provides insight on how to measure the characteristics of these unusual compounds on nets when used by communities. It is important to monitor effectiveness over 3 years lifespan because effectiveness is likely to change over time. It is important to decide how, where and when the main categories of bi-treated LN should be deployed to maximize effectiveness and resistance management potential. Insecticide combinations, as with drug combinations in the example of antimalarial therapy, are considered the best way to reduce selection pressure for resistance but the LN may differ in this capability. To address these issues we propose a four-arm randomized non-inferiority trial in 56 villages comparing the two PBO-LN types 1/ reference PBO-LN (Olyset Plus) and 2/ mosaic PBO-LN (PermaNet 3.0), and the two mixture-LN 3/ PPF-LN (Olyset Duo) and 4/ CFP-LN (Interceptor G2). The trial will demonstrate whether the mixture PPF-LN and CFP-LN provide similar or greater protection against malaria transmission than the reference PBO-LN. It will show whether mosaic PBO-LN provides equivalent protection to the reference PBO-LN. It will show whether bi-treated LN will reduce or prevent the selection of resistance. Health economic analysis will define which interventions are cost effective. The trial findings will guide national malaria control and international agencies (Global Fund, President's Malaria Initiative, WHO) on malaria control strategy, effectiveness of different types of bi-treated LN, cost effectiveness and deployment options to maximize impact against resistance.