In the myth of Sisyphus, French philosopher Albert Camus illustrated the hopelessness and exhaustion of a man pushing a boulder up a steep hill. The hill was an obstacle in Sisyphus’ path. The further he pushed the boulder, the more progress he made. However, his task became continuously more strenuous and exhausting, causing his strength to wane the nearer he was to the top.
Two obvious solutions to Sisyphus’ pain involve either attempting to reduce the weight of the boulder or to increase his own strength. There is, however, another angle at which to pragmatically view this challenge. One can conversely address the difficulty caused by the roadblock itself: the incline of the hill. On a flat plain, when applying the same amount of force, with the same weight of boulder, Sisyphus’ task would become easier to accomplish. This third way of viewing the problem and a closer look at resistance serves as an interesting case study in the context of malaria.
Malaria is a challenging issue in Rwanda for a plethora of reasons, but one of the most crucial and topical issues is that of emerging resistance to insecticides among Anopheles mosquitoes.
One of the most effective methods of preventing malaria in Rwanda, is through distribution and use of ITN (Insecticide treated nets), coupled with behavior change campaigns to help communities see the value and effectiveness of using them. ITNs are treated with an agent called Permethrin, which greatly increases mosquito mortality rates as mosquitoes rest on the outside of the treated nets.
Conducting mass distributions of ITNs is a pivotal step in reducing malaria in communities, and although malaria mortality rates greatly declined in Rwanda from 2005 to 2011 (and continue to decline at a slower rate currently), reducing the number of cases has been a hard-fought battle.
In 2017, Rwanda recorded over 4.7 million cases of malaria. (Rwanda Malaria Operational Plan FY 2019). As these cases increase, there are many concerns regarding the growing and evolving nature of insecticidal resistance. Some mosquitoes have developed an enzyme to combat the effects of permethrin, protecting the life of the Anopheles mosquito from the effects of the pyrethroid-based insecticide.
Let’s return to our friend Sisyphus for some insight.
If Sisyphus’ strength remained the same, and the burden of the boulder was unchanging, changing the level of incline could still help solve his eternal struggle to move the boulder forward past the steep hill in front of him and onward in his journey.
Sisyphus’ strength was not sufficient to move, let alone maintain, the burden he pushed when coupled with the increased incline of the hill.
Like Sisyphus, organizations working in malaria prevention require a synergist to address such a formidable and steep roadblock such as insecticide resistance. Similar to the alarming prospect of the boulder rolling all the way back down the hill, insecticide resistance has the potential to negate progress already made towards malaria elimination around the world. It becomes clear, that this complex factor of resistance must be directly addressed. In this case, a synergist is required.
A synergist is an agent that increases the effectiveness of another agent when combined with it. (Webster) In other words, permethrin needs an ally; a chemical agent to weaken the mosquitoes’ resistance that has been evolving and adapting to treated nets for as long as they have been used to prevent malaria.
One such ally/synergist has arrived in the form of piperonyl butoxide, otherwise known as PBO.
PBO does not kill mosquitoes directly. When infused with insecticide, it does however, break down an enzyme in mosquitoes that establishes a level of resistance to permethrin, the main agent used to treat mosquito nets. (Gleave)
“Piperonyl butoxide (PBO) is a synergist that inhibits specific metabolic enzymes within mosquitoes and has been incorporated into pyrethroid‐LLINs to form pyrethroid‐PBO nets.” (Rwanda Malaria Operational Plan FY 2019).
Simply stated, adding PBO elements to treated nets (LLINs) improves their efficacy in reducing mosquito populations.
Pilot Testing: The Findings
Gleave Et al.’s systematic review “Piperonyl butoxide (PBO) combined with pyrethroids in insecticide‐treated nets to prevent malaria in Africa” gives us an overview of the actual effectiveness of PBO in reducing malaria burden in areas of high pyrethroid resistance.
The trial was conducted with 3,966 people with an outcome of decreased malaria prevalence. The malaria prevalence in the decreased from 527 individuals to 211… With an unwashed Pyrethroid-PBO net, the mortality rate of mosquitoes was 438 per 1000, versus 238 per 1000 with a standard LLIN. This was true in an area of high insecticide resistance. (Gleave)
Other village trials were conducted in less resistant areas, and PBO was found to have less/if any effect on mosquito mortality rates. Results of the systematic review suggest that PBO has high efficacy only when implemented in an area with highly pyrethroid resistant mosquitoes.
Even in areas of moderate insecticide resistance, PBO influence was not shown to have a statistically significant effect on mosquito mortality: “There may be little or no difference in the effect of washed pyrethroid‐PBO nets on mosquito mortality com-pared to standard washed LLINs (washed) in areas of moderate insecticide resistance.”
Another interesting side-note; efficacy of the PBO agent may decrease over the course of multiple washings of the ITN:
“However this effect on mosquito mortality, which is important for the community‐level protection afforded by LLIN usage (Hawley 2003; Maxwell 2002), is not sustained when nets have been washed multiple times. We classified mosquitoes as being highly resistant if fewer than 30% were killed in a standard bioassay. When mortality rates exceeded 30%, there was little evidence that pyrethroid‐PBO nets provided greater personal protection or resulted in greater mosquito mortality than standard pyrethroid‐only nets.”
Resistance in Rwanda: Where do we stand?
PBO dramatically affects areas with high resistance to pyrethroids, while, according to Gleave’s village trials, has low impact on low and moderate resistance areas. Subsequently, if an area has high insecticidal resistance among mosquito populations, PBO impact will be high. This is especially important to consider in the context of Rwanda where PBO was found to be highly effective and impactful.
“PBO synergist assays conducted by MOPDD in four districts from four provinces in 2017 all demonstrated pyrethroid resistance with restoration of susceptibility to 100 percent on addition of PBO. Similar results were found with PBO assays in eight districts from the same four provinces in 2015. (Rwanda MOP 2019)”
PBO-pyrethroid nets had an immediate and dramatic effect on mosquito mortality rates in Rwanda’s Bugesera district, with respect to mosquito mortality (Rwanda MOP 2019).
PMI will also continue to investigate the effectiveness of PBO, especially since its effectiveness changes with time. Measuring any impact on malaria prevalence in areas employing PBO in-fused nets will be crucial information moving forward.
Many strategies are necessary to ensure proper implementation of the program: “PMI will include data analysis for the planned PBO net pilot, using community-level surveillance and technical assistance for district level epidemiological trend analysis, among other activities to assess the program.” (Rwanda Malaria Operational Plan FY 2019)
In conclusion, PBO LLINs are a potentially groundbreaking step in the work to reduce malaria cases in Rwanda. Though this mass net distribution campaign will likely be very effective, without behavior change communication (BCC) and effective mobilization of communities to responsibly and correctly use their nets, the nets may prove to have less of an impact. Their durability must be closely monitored in real world settings, which will provide valuable data for the Ministry of Health as they move forward with these programs.
Malaria prevention is expensive. The greater amount of cases, the greater need for novel insecticide combinations and a robust malaria prevention strategy. With increased insecticide use, come more opportunities for insecticide resistance. Unlike the hopeless state of Sisyphus, however, through partnerships with the Ministry of Health and the WHO, as well as studies and village trials from pilot programs like Gleaves Et al., Rwanda has the potential to combat the obstacle of insecticide resistance more effectively through PBO.
Insecticide is not the only obstacle faced in the quest for malaria elimination, but it is a formidable roadblock that can be managed and removed, saving poor Sisyphus from the exhaustion of a hopeless struggle.
1“Pyrethroid‐PBO nets are currently produced by four LLIN manufacturers and, following a recommendation from the World Health Organization (WHO) in 2017, are being included in distribution campaigns in countries.”
2 “We included laboratory trials, experimental hut trials, village trials, and randomized clinical trials with mosquitoes from the Anopheles gambiae com-plex or Anopheles funestus group.”
3 “One village trial examined the effect of pyrethroid‐PBO nets on malaria infection prevalence in an area with highly pyrethroid‐resistant mosquitoes. The latest endpoint at 21 months post‐intervention showed that malaria prevalence probably decreased in the intervention arm (OR 0.40, 95% CI 0.20 to 0.80; 1 trial, 1 comparison, moderate‐certainty evidence).”
4 “The WHO recommendation is that countries should consider deployment of this new product class in areas with intermediate levels of pyrethroid resistance but calls for further evidence, including data from a second clinical trial.”
5 PMI will procure approximately 2.6 million PBO LLINs for Rwanda as part of the 2019 mass campaign, as well as for routine districution in districts receiving PBO LLINs during the campaig. With FY 2019 funding, PMI will procure 1 million LLINs for distribution through ANC and expanded program for immunization clinics.
1. Gleave K, Lissenden N, Richardson M, Choi L, Ranson H. Piperonyl butoxide (PBO) combined with pyrethroids in insecticide-treated nets to prevent malaria in Africa. Cochrane Database of Systematic Reviews 2018, Issue 11. Art. No.: CD012776. DOI: 10.1002/14651858.CD012776.pub2.
2. WHO: World malaria report 2018. Available: https://www.who.int/malaria/publications/world-malaria-report-2018/report/en/. Accessed 2019 Feb 1.
3. President’s Malaria Initiative (PMI). Malaria Operational Plan: Rwanda FY 2019. Washington, DC: PMI, 2019. Available: https://www.pmi.gov/docs/default-source/default-document-library/ malaria-operational-plans/fy19/fy-2019-rwanda-malaria-operational-plan.pdf Accessed 2019 Feb 1.