Modelling the impact of antimalarial quality on the transmission of sulfadoxine-pyrimethamine resistance in Plasmodium falciparum

Abstract

Background: The use of poor quality antimalarial medicines, including the use of non-recommended medicines for treatment such as sulfadoxine-pyrimethamine (SP) monotherapy, undermines malaria control and elimination efforts. Furthermore, the use of subtherapeutic doses of the active ingredient(s) can theoretically promote the emergence and transmission of drug resistant parasites.

Methods: We developed a deterministic compartmental model to quantify the impact of antimalarial medicine quality on the transmission of SP resistance, and validated it using sensitivity analysis and a comparison with data from Kenya collected in 2006. We modelled human and mosquito population dynamics, incorporating two Plasmodium falciparum subtypes (SP-sensitive and SP-resistant) and both poor quality and good quality (artemether-lumefantrine) antimalarial use.

Findings: The model predicted that an increase in human malaria cases, and among these, an increase in the proportion of SP-resistant infections, resulted from an increase in poor quality SP antimalarial use, whether it was full- or half-dose SP monotherapy.

Interpretation: Our findings suggest that an increase in poor quality antimalarial use predicts an increase in the transmission of resistance. This highlights the need for stricter control and regulation on the availability and use of poor quality antimalarial medicines, in order to offer safe and effective treatments, and work towards the eradication of malaria.

Keywords: Antimalarial quality; Deterministic compartmental model; Drug resistance; Falsified antimalarial medicine; Plasmodium falciparum malaria; Substandard antimalarial treatments.

Fig. 1

A summary of the structure of the mathematical model showing the movement between compartments of SP-sensitive and SP-resistant Plasmodium falciparum in humans and female Anopheles mosquitoes (blue solid line). The transmission of gametocytes (infected human to susceptible mosquito) and sporozoites (infected mosquito to susceptible human) during a blood meal, is depicted by the red dotted line for SP-sensitive, and a dark green dotted line for SP-resistant.

Fig. 2

(A) The impact of antimalarial quality on the average duration of gametocyte carriage in humans. (B–C) The impact of antimalarial quality on the infectiousness of humans to mosquitoes during a blood meal (probability), of (B) SP-sensitive and (C) SP-resistant gametocytes. Changes in the percentage use of full-dose SP monotherapy (${\theta }_m$, orange line) were adjusted for the use of 3% half-dose SP monotherapy $\left({\theta }_p\right)$, 20% receiving no treatment $\left({\theta }_n\right)$ and the remainder AL treatment $\left({\theta }_q\right)$. Likewise, changes in half-dose SP monotherapy use (θ_p, purple line) were adjusted for ${\theta }_m=7\%,{\theta }_n=20\%$ and ${\theta }_q=$ remainder; changes in those receiving no treatment (θ_n, blue line) were adjusted for ${\theta }_m=7\%,{\theta }_p=3\%$ and ${\theta }_q=$ remainder; and changes in AL use (θ_q, green line) were adjusted for ${\theta }_p=3\%,{\theta }_n=20\%$ and ${\theta }_m=$ remainder. The 2006 model baseline (black line) corresponds to ${\theta }_q=70\%,{\theta }_m=7\%,{\theta }_p=3\%$ and ${\theta }_n=20\%$.

Fig. 3

(A) The impact of antimalarial quality on the predicted number of human malaria cases in 2006. (B) The impact of antimalarial quality on the total proportion of SP-resistant infections in humans. Changes in the percentage use of full-dose SP monotherapy (${\theta }_m$, orange line) were adjusted for the use of 3% half-dose SP monotherapy $\left({\theta }_p\right)$, 20% receiving no treatment $\left({\theta }_n\right)$, and the remainder AL treatment $\left({\theta }_q\right)$. Likewise, changes in half-dose SP monotherapy use (θ_p, purple line) were adjusted for ${\theta }_m=7\%,{\theta }_n=20\%$, and ${\theta }_q=$ remainder; changes in those receiving no treatment (θ_n, blue line) were adjusted for ${\theta }_m=7\%,{\theta }_p=3\%$ and ${\theta }_q=$ remainder; and changes in AL use (θ_q, green line) were adjusted for ${\theta }_p=3\%,{\theta }_n=20\%$, and ${\theta }_m=$ remainder. The 2006 model baseline (black line) corresponds to ${\theta }_q=70\%,{\theta }_m=7\%,{\theta }_p=3\%$, and ${\theta }_n=20\%$. Model simulations run for 365 days.

Fig. C2.2.1

The daily P. chabaudi gametocyte density in mice post-pyrimethamine treatment for (A) pyrimethamine-sensitive gametocytes, (B) pyrimethamine-resistant gametocytes, and (C) mixed infection gametocytes. The purple line denotes the gametocyte density for a 100% pyrimethamine treatment. The green line denotes the gametocyte density of 37.5% of a full dose of pyrimethamine treatment for (A) and 50% of a full dose of pyrimethamine treatment for (B) and (C). Data provided by Huijben et al., 2013, Huijben et al., 2010a, Huijben et al., 2010b.

Fig. C3.2.1

The proportion of infected mosquitoes when exposed to (A) SP-sensitive P. falciparum gametocytes, (B) SP-resistant P. falciparum gametocytes (108 mutants only) and (C) SP-resistant P. falciparum gametocytes (51 and 108 mutants), from infected humans over five years of age on the Pacific Coast of Columbia, who were treated with SP monotherapy. Estimates obtained from Fig. 1 of Méndez et al. (2007). Note: length of data collection was 28 days.

Fig. C3.2.2

The average gametocyte density per day in mice infected with P. Chabaudi and treated with pyrimethamine. The blue line denotes the pyrimethamine-sensitive (W) gametocyte density associated with pyrimethamine treatment. In like manner, the red line denotes the pyrimethamine-resistant (R) gametocyte density, and the green dotted line denotes the mixed infection (WR) gametocyte density. Data provided by Huijben et al. (2013).

Fig. C3.2.3

Average gametocyte density of P. Chabaudi infected mice with (A) pyrimethamine-sensitive gametocyte treated with full-dose pyrimethamine; (B) pyrimethamine-sensitive gametocyte treated with half-dose pyrimethamine; (C) pyrimethamine-resistant gametocyte treated with full-dose pyrimethamine; (D) pyrimethamine-resistant gametocyte treated with half-dose pyrimethamine; (E) mixed infection gametocyte treated with full-dose pyrimethamine; (F) mixed infection gametocyte treated with half-dose pyrimethamine. These graphs are produced using data from Huijben et al. (2013).

Fig. C3.3.1

Combining past studies results for gametocyte infectivity to mosquitoes following AL treatment in children, as reported by Bousema et al., 2006, Sawa et al., 2013, Sutherland et al., 2005.