The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: a meta-analysis of individual patient data

Abstract

Background: The majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programs combined with sulfadoxine-pyrimethamine. While artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas.

Methods: We analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n = 4214 individuals). The time to PCR-confirmed reinfection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to reinfection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment.

Results: We estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7-15.7) for AL and 15.2 days (95% CI 12.8-18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7-18.6 days for AL and 10.2-18.7 days for AS-AQ. Significant predictors of time to reinfection in multivariable models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated (<=20% 86Y and 76T mutants, respectively), AS-AQ provided ~ 2-fold longer protection than AL. Conversely, at a higher prevalence of 86Y and 76T mutant parasites (> 80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protection could alter population-level clinical incidence of malaria by up to 14% in under-5-year-old children when the drugs were used as first-line treatments in areas with high, seasonal transmission.

Conclusion: Choosing a first-line treatment which provides optimal post-treatment prophylaxis given the local prevalence of resistance-associated markers could make a significant contribution to reducing malaria morbidity.

Keywords: Amodiaquine; Artemisinin; Crt; Drug; Lumefantrine; Malaria; Mathematical model; Trial; mdr1.

Conflict of interest statement

LCO declares prior grant funding from the World Health Organization in addition to the funding already declared in the acknowledgements. The other authors declare that they have no competing interests.

Figures

Fig. 1

Duration of post-treatment prophylaxis. Posterior estimates of the median duration of protection (a) and the proportion of the population still having drug levels which would protect them from reinfection, over time since first dose with either AS-AQ (b) or AL (c). In b and c, the solid lines show the median estimate across trial sites, while the dotted lines show the different estimates for each of the 12 trial sites. The equations of the lines in b and c are reverse cumulative gamma distributions and can be implemented for example in R as 1-pgamma(t, shape = r, scale = λ), where t is time in days, and r and λ are the shape and scale parameters of the gamma distribution, respectively. For AL, r = 93.5 and mean λ = 0.139. For AS-AQ, r = 16.8 and mean λ = 0.906. The mean of each gamma distribution rλ gives the duration of protection from each drug. The site-specific lines can be calculated using the median durations of prophylaxis in Table 1, and the same shape parameter (assumed not to vary between sites for each drug)

Fig. 2

Time to reinfection after treatment and model fits. Proportion of patients reinfected (after PCR correction) during follow-up after treatment at day 0 with AL (blue) or AS-AQ (green) in each of the 12 trial sites. Circles show data with 95% CI, and the lines are the fits of the hidden semi-Markov model in each site. The AL trial arms include in total 2086 individuals and 642 reinfections and the AS-AQ trial arms, 2128 individuals and 538 reinfections

Fig. 3

Trial-specific EIR estimates. Prior and posterior estimates of the EIR at each trial site. The prior predictions are based on Malaria Atlas Project data [28]

Fig. 4

Duration of protection after treatment with a, c AS-AQ and b, d AL, according to local pfmdr1 N86Y (a, b) and pfcrt K76T mutation prevalence (c, d). Median posterior estimates of duration of protection from hidden Markov model analysis are shown (points) with 95% credible intervals (vertical lines). Local pfmdr1 N86Y and pfcrt K76T mutation prevalences are from matched surveys within 1 year and 300 km in the same country as each trial. Horizontal lines indicate the 95% confidence intervals of the mutation prevalence estimates

Fig. 5

Duration of prophylaxis and impact on clinical incidence in under 5-year-old children of using AS-AQ rather than AL as first-line treatment, estimated by the transmission model analysis, contrasting areas with low (a–c) or high (d–f) pfmdr1 86Y and pfcrt 76T prevalence. a The estimated proportion of individuals protected over time since treatment by AL or AS-AQ in Gourcy, Burkina Faso, where 86Y and 76T prevalences are low (18% and 25%, respectively) and amodiaquine provides longer chemoprophylaxis than lumefantrine or d Nimba, Liberia, where 86Y and 76T prevalences are high (69% and 95%, respectively) and the prophylactic times are reversed so that lumefantrine provides longer chemoprophylaxis than amodiaquine. b, c The model-estimated impact in children aged 0–5 years of using AS-AQ rather than AL as first-line treatment in the whole population, using the prophylactic profiles in a. The outcomes are b the difference and c the % difference in the cumulative number of clinical episodes occurring during the 5 years after implementing either drug at 80% coverage; here AS-AQ is predicted to decrease clinical incidence compared with AL. Orange bars show the impact in non-seasonal settings, while red shows the impact in a seasonal setting (see “Methods”). e, f The corresponding results using the prophylactic profiles in d; here AS-AQ is predicted to increase clinical incidence compared with AL