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.

We propose a cluster randomised trial which compares four vector control interventions to prevent malaria in areas where vector mosquitoes are resistant to pyrethroids and the standard long-lasting insecticide treated nets (LN) are unable to control malaria adequately. These interventions are based on novel bi-treated LNs incorporating mixtures of insecticides or insecticide synergists to improve efficacy.
The proposed trial will be a four-arm, single blinded, non-inferiority cluster-randomized trial with the following arms:
1. Control arm: Olyset Plus LN (Sumitomo Chemicals) is a LN combining a synergist PBO and pyrethroid permethrin incorporated in the polyethylene fibres on all 5 panels.
2. Intervention arm 1: Permanet 3.0 (Vestergaard) is a mosaic LN consisting of polyester on the 4 side panels coated with pyrethroid deltamethrin. PBO is restricted to the top panel made of polyethylene fibres and incorporating also deltamethrin.
3. Intervention arm 2: Olyset Duo is a bi-treated polyethylene LN incorporating permethrin and an insect growth regulator pyriproxifen (PPF) that sterilises mosquitoes that contact the net.
4. Intervention arm 3: Interceptor G2 is a mixture LN made of polyester and coated with a wash-resistant formulation of chlorfenapyr (CFP) and alpha-cypermethrin pyrethroid.
The proposal will address the following questions: 1/ Do new generation of LN that include a pyrethroid and a novel insecticide (PPF or CFP) provide similar or better protection to the PBO-synergist LN against malaria transmitted by pyrethroid resistant vectors? 2/ Does mosaic PBO-LN and PBO-LN on all panels provide the same protection? 3/ Which LN (CFP, PBO or PPF) is more effective at preventing malaria and managing resistance?
Evaluation of the effectiveness of each LN will be based 1/ on malaria prevalence in children under 15 years, 2/ malaria incidence and transmission and 3/ selection of insecticide resistance. Cost effectiveness of each LN will also be compared.

This project will have impacts on malaria control policy and practice, both national and international, benefiting public sector, private sector manufacturers, and community recipients.

The strategy of the Tanzania Malaria Control Program (NMCP) is flexible and evidence-based and incorporates new tools of proven impact. With the reduction in malaria burden achieved in recent years but the spread of resistance, the NMCP accepts a more tailored approach than blanket distribution of standard LN. Together we demonstrated that standard LN were no longer effective in the northwest and that PBO-LN would provide improved protection. During the preparation of this proposal, we selected with NMCP and other stakeholders the most promising types of bi-treated LN to be evaluated. Each of these bi-treated LN could make a difference in the control of resistant vectors but they need to be tested comparatively in large scale trial. This should widen the arsenal of LN products and help NMCPs to take programmatic decisions on how to deploy each LN to best effect. The trial findings have regional implications. Any data or strategy emerging will be relevant to NMCPs of neighbouring Kenya, Uganda, Burundi, DRC and Malawi, all of which have a growing resistance problem.

The trial will have beneficial impact on the private sector. The aim is not to make any bi-treated LN redundant but to establish how well each would control transmission caused by a given species (funestus, gambiae, or arabiensis) and individual capacity to prevent resistance selection. Each may differ with respect to species, selection of resistance, and environment. Each may have a useful niche. It is more important to keep the innovatory manufacturers in business than create a winner-takes-all situation. The present reality is market domination from generic LN. This has enabled universal coverage. But the future need is for LN that control resistant mosquitoes. Capacity to innovate requires depth in chemistry, in formulation technology, in polymer technology. Generic companies lack that capacity. The stimulus to innovate from IVCC and LSHTM has led to several promising products but this is not enough. To take the most promising to market requires demonstration in formal RCT of how well each product can control malaria. A more diverse and equitable market will follow, keep the innovators innovating, and help us to keep us ahead of resistance. The first step in that process is demonstration of impact.

The innovatory companies are willing to provide their LN at cost-of-goods. But a free donation is a big ask when their market share is so small. In the final analysis, this trial will shift the market to addressing the new public health need, broaden the range of players and products.

The project has representatives of PMI/CDC, WHO and Global Fund on the TSC who will keep their agencies abreast of the findings. If shown to be an improvement the agencies would switch product or revise strategy.

WHO calls for the development and evaluation of non-pyrethroid LLINs including PBO-LN. The WHO Evidence Review Group states that PBO-LN appear to have an increased efficacy in certain settings, the evidence is too limited to justify a complete switch, neither is there evidence to assume greater utility in a resistance management strategy. These new types of bi-treated LN have more complex mode of action and their full effectiveness can only be assessed by large scale CRT with epidemiological endpoints. The proposed trial would therefore help WHO to meet its recommendation.

This research will first and foremost benefit the community. Standard LN are no longer providing adequate protection in certain areas of Tanzania. The same phenomenon is being observed in neighbouring countries. It is time to switch to more effective LN and the present study will demonstrate which types of bi-treated LN are appropriate.