Epidemiological impact of insecticide resistance

SPEAKER: I would like to review the evidence that resistance to the insecticides that are commonly used in vector control are resulting in changes in effectively disease morbidity, mortality, and infection rates. I’ll focus on the anopheles malaria system, as this is where most evidence have been collected. The context of this lecture is that over the last few decades, we’ve seen a massive increase in the number of people in vector borne disease endemic areas who were protected by insecticide based interventions. As an illustration, here’s some data collected by the World Health Organisation.

In the figure on the right, we see the change between 2000-2010 in the proportion of household by country in sub-Saharan Africa who have at least one insecticide treated bed net. The darker tones of green indicating a higher proportion. The map on the right show similar data for indoor residual spraying of insecticides with large numbers of people, particularly in eastern Africa, being protected by IRS. Given the large numbers of people protected by insecticide based vector control, the emergence of insecticide resistance in malaria transmitting mosquitoes could render these control methods useless. That’s obviously a major concern. What we wish to avoid is another control failure incident, like that was observed in South Africa.

The graph shows the annual number of cases in South Africa of malaria, principally in KwaZulu-Natal between 1972 and 2009. What is clear, in the mid to late 1990s, a mild increase in the number of malaria cases coincided with the emergence of mosquitoes which were resistant to pyrethroid insecticides that was used for IRS. With observational time series data like this, it’s impossible to determine causality, but it’s certainly highly likely that the emergence of resistance was a major contributor to the spike in numbers. So insecticide may be impacting the success of control programmes, but how big a problem could it be? Could advances in vaccines, anti-malarial drugs, or health systems strengthening compensate for this loss of ineffective mosquito control?

The answer to that is an unequivocal no. The graph on the left illustrates just how important vector control is. It is estimated that over 250 million clinical cases of malaria have been averted in the period of 2000 to 2015, with ITN responsible for the vast majority of the reduction, approximately 68%. The graph to the right show data from a modelling exercise that attempted to estimate how resistance could impact malarial deaths, and revealed that if an insecticide used on ITNs failed due to mosquito resistance, there could be a predicted increase in the annual number of malaria deaths between 100 and 260 thousands. However, definitive evidence of the impact is lacking. And most of our data are drawn from longitudinal observational studies.

These data from Uganda show how in an area where the malaria vectors Anopheles gambiae and Anopheles rhodesiensis are resistant to the pyrethroid insecticide used on bed nets. The graphs on the left are showing test data from a WHO tube test. On the right, we see three different measures of malaria transmission that are not perturbed when pyrethroid ITNs were distributed to the community, as shown in the yellow bar. In contrast, we see a marked reduction with the different insecticide to which the mosquitoes were 80 to 100% susceptible. And this was applied using IRS, and shown in the pink box. This again is highly suggestive that ITNs are working sub-optimally in areas of pyrethroid resistance.

But the WHO wanted a definitive study which could unequivocally demonstrate and quantify the impacts of resistance. And so they coordinated a five country study. The study ran between 2009 and 2016, in Benin, Cameroon, India, Kenya, and Sudan, and conducted a series cross-sectional prevalence areas, malaria infection disease cohorts, alongside contemporaneous estimation of insecticide resistance in the primary malaria vectors. There were nearly 280 study communities with over 50,000 children tested for parasitaemia and the resistant status of over 80,000 mosquitoes assessed. This is the schematic of what happened in each study community. In each cluster or village, children were tested for malaria infection or disease. And data collected on whether they slept under an insecticide treated net.

Alongside this, and in the same clusters, entomology teams would collect mosquitoes and quantify the resistance of the population to the pyrethroid insecticide used in ITN. What it shows is that in almost all communities, and in the overall five country analysis, the prevalence of malaria was lower in those children who reportedly slept under the net rather than those that did not. Therefore, even in areas of intense resistance it is still better to use your net. This does not mean that ITNs are effective as they once were. But they still offer some protection. It also reflects the way were tuning estimate resistant may not be sensitive enough. So even in areas of resistance, we would encourage communities to use insecticide nets.

However, more recent evidence shows how some new net types may have a superior impact on malaria prevalence. These new net types incorporate a compound called PBO which at least in part disables some of the enzymes that detoxify insecticides and enable mosquitoes to become resistant. This study showed the net types caused a significant reduction in parasite rates in children, and that the effect was sustained for at least 21 months post distribution. Similar results have been observed in another trial in Uganda. So to conclude, the trials in new net types suggest that we are seeing an impact of resistance on vector control. But as demonstrated by the five country trial, this is not yet at a catastrophic level.

And even conventional ITNs still deliver a measurable benefit. However, we should not be complacent and must work to bring new vector control technologies, including non-insecticidal products, to market as soon as possible.