Research Article: Modelling the Impact of Artemisinin Combination Therapy and Long-Acting Treatments on Malaria Transmission Intensity

Date Published: November 25, 2008

Publisher: Public Library of Science

Author(s): Lucy C Okell, Chris J Drakeley, Teun Bousema, Christopher J. M Whitty, Azra C Ghani, Steven Riley

Abstract: BackgroundArtemisinin derivatives used in recently introduced combination therapies (ACTs) for Plasmodium falciparum malaria significantly lower patient infectiousness and have the potential to reduce population-level transmission of the parasite. With the increased interest in malaria elimination, understanding the impact on transmission of ACT and other antimalarial drugs with different pharmacodynamics becomes a key issue. This study estimates the reduction in transmission that may be achieved by introducing different types of treatment for symptomatic P. falciparum malaria in endemic areas.Methods and FindingsWe developed a mathematical model to predict the potential impact on transmission outcomes of introducing ACT as first-line treatment for uncomplicated malaria in six areas of varying transmission intensity in Tanzania. We also estimated the impact that could be achieved by antimalarials with different efficacy, prophylactic time, and gametocytocidal effects. Rates of treatment, asymptomatic infection, and symptomatic infection in the six study areas were estimated using the model together with data from a cross-sectional survey of 5,667 individuals conducted prior to policy change from sulfadoxine-pyrimethamine to ACT. The effects of ACT and other drug types on gametocytaemia and infectiousness to mosquitoes were independently estimated from clinical trial data. Predicted percentage reductions in prevalence of infection and incidence of clinical episodes achieved by ACT were highest in the areas with low initial transmission. A 53% reduction in prevalence of infection was seen if 100% of current treatment was switched to ACT in the area where baseline slide-prevalence of parasitaemia was lowest (3.7%), compared to an 11% reduction in the highest-transmission setting (baseline slide prevalence = 57.1%). Estimated percentage reductions in incidence of clinical episodes were similar. The absolute size of the public health impact, however, was greater in the highest-transmission area, with 54 clinical episodes per 100 persons per year averted compared to five per 100 persons per year in the lowest-transmission area. High coverage was important. Reducing presumptive treatment through improved diagnosis substantially reduced the number of treatment courses required per clinical episode averted in the lower-transmission settings although there was some loss of overall impact on transmission. An efficacious antimalarial regimen with no specific gametocytocidal properties but a long prophylactic time was estimated to be more effective at reducing transmission than a short-acting ACT in the highest-transmission setting.ConclusionsOur results suggest that ACTs have the potential for transmission reductions approaching those achieved by insecticide-treated nets in lower-transmission settings. ACT partner drugs and nonartemisinin regimens with longer prophylactic times could result in a larger impact in higher-transmission settings, although their long term benefit must be evaluated in relation to the risk of development of parasite resistance.

Partial Text: Since 2000, artemisinin combination therapies (ACTs) have become widely adopted as first-line treatment policy for uncomplicated P. falciparum malaria in many endemic countries in response to parasite resistance that rendered previous first line treatments ineffective [1,2]. A secondary factor in the policy choice of ACT has been the proven ability of the artemisinin component to reduce patient gametocytaemia and infectiousness more than previous first-line treatments [3–6], which shows potential to translate into a reduction in overall transmission intensity as use of ACT is scaled up [7]. With the renewed interest in minimising transmission and moving toward malaria elimination [8], it is increasingly important to evaluate the ability of antimalarial treatments not only to cure disease, but also to reduce transmission. Understanding how pharmacological properties of ACT and other antimalarials affect transmission, as well as choice of delivery strategies, can help to maximise the impact of available resources.

Our model shows the potential for an appreciable impact of ACT on malaria transmission at current rates of antimalarial treatment in our study area of Tanzania. The predicted reductions in prevalence of slide-positive infection at 100% coverage are between 11.5% and 52.9%, which compare with 13%–42% achieved by insecticide-treated bed nets (ITNs) in trial settings [43] and, as such, ACT could form an important part of a transmission reduction programme. The estimated reductions in rates of clinical episodes of 21.1%–52.5% with a short-acting ACT are lower than pooled estimates of ITN impact of 50%–62% [43]. In higher-transmission settings (>20% baseline slide-prevalence), ACT is predicted to have its smallest relative impact on transmission as found in a previous model looking at SP-AQ [17], due to a combination of a lower proportion of infections being treated and the different dynamics of infection prevalence (Figure 3A; Figure IV in Text S1). However, in terms of public health impact, the absolute number of clinical episodes prevented by introducing ACT in high-transmission settings was much greater, and the courses of treatment required per episode indirectly averted was substantially lower given current treatment rates across settings. Furthermore, the direct benefits of effective clearance of parasites for infected individuals would be considerable. More widespread use of diagnostic tools prior to treatment is predicted to increase the efficiency of ACT in reducing transmission per treatment course, especially in lower-transmission settings, although it could result in some reduction in the total impact, as previously suggested [45]. Depending on how quickly ACTs are made widely available, significant impact could be seen within a few weeks in higher-transmission settings but would occur over several months in lower-transmission settings. Our analysis deliberately represents an ideal scenario in order to estimate the maximum potential for ACT impact, whilst in reality the difficulties of imperfect patient adherence and of achieving good coverage in all health sectors [1,46] would reduce the speed and magnitude of transmission reductions, potentially substantially, as seen with ITNs outside trial settings.