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Contrasting benefits of different artemisinin combination therapies as first-line malaria treatments using model-based cost-effectiveness analysis.

Okell LC, Cairns M, Griffin JT, Ferguson NM, Tarning J, Jagoe G, Hugo P, Baker M, D'Alessandro U, Bousema T, Ubben D, Ghani AC - Nat Commun (2014)

Bottom Line: DHA-PQP has a modestly higher estimated impact than AL in 64% of the population at risk.Given current higher cost estimates for DHA-PQP, there is a slightly greater cost per case averted, except in areas with high, seasonally varying transmission where the impact is particularly large.We find that a locally optimized treatment policy can be highly cost effective for reducing clinical malaria burden.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College, London W2 1PG, UK.

ABSTRACT
There are currently several recommended drug regimens for uncomplicated falciparum malaria in Africa. Each has different properties that determine its impact on disease burden. Two major antimalarial policy options are artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PQP). Clinical trial data show that DHA-PQP provides longer protection against reinfection, while AL is better at reducing patient infectiousness. Here we incorporate pharmacokinetic-pharmacodynamic factors, transmission-reducing effects and cost into a mathematical model and simulate malaria transmission and treatment in Africa, using geographically explicit data on transmission intensity and seasonality, population density, treatment access and outpatient costs. DHA-PQP has a modestly higher estimated impact than AL in 64% of the population at risk. Given current higher cost estimates for DHA-PQP, there is a slightly greater cost per case averted, except in areas with high, seasonally varying transmission where the impact is particularly large. We find that a locally optimized treatment policy can be highly cost effective for reducing clinical malaria burden.

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Related in: MedlinePlus

PKPD results.Concentration-effect curves for piperaquine (a) and lumefantrine (b) estimated from model fitting, with 95% CI. Piperaquine concentrations relate to capillary measurements and lumefantrine concentrations to venous measurements. Probability of protection from reinfection over time since the first dose based on pharmacokinetic models: piperaquine (c,e) and lumefantrine (d,f), simulations in children <10 years in the clinical trials (c,d) and in all age–weight groups based on Tanzanian bodyweight distribution (e,f). Probability of protection from reinfection over time since the first dose with piperaquine (g) or lumefantrine (h)—model fits and 95% CI using a Weibull survival function instead of pharmacokinetic models.
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f2: PKPD results.Concentration-effect curves for piperaquine (a) and lumefantrine (b) estimated from model fitting, with 95% CI. Piperaquine concentrations relate to capillary measurements and lumefantrine concentrations to venous measurements. Probability of protection from reinfection over time since the first dose based on pharmacokinetic models: piperaquine (c,e) and lumefantrine (d,f), simulations in children <10 years in the clinical trials (c,d) and in all age–weight groups based on Tanzanian bodyweight distribution (e,f). Probability of protection from reinfection over time since the first dose with piperaquine (g) or lumefantrine (h)—model fits and 95% CI using a Weibull survival function instead of pharmacokinetic models.

Mentions: The cumulative rate of PCR-confirmed reinfection in the clinical trial data was generally higher in children treated with AL compared with DHA–PQP (Fig. 1), with the difference tending to be larger in higher transmission sites due to more reinfection events. The best-fitting model predictions from our PKPD model were within the 95% confidence intervals (CI) of the large majority of data points (Fig. 1). The concentration at which each antimalarial prevents 50% of new infections from successfully establishing as blood-stage infections was estimated at 22.1 ng ml−1 for piperaquine and 332.3 ng ml−1 for lumefantrine (Fig. 2a,b; Table 1). In the study populations in which the clinical trials were conducted, the mean number of days for which piperaquine prevented 90% or more reinfections was 26.2 (range 13.6–45.0 days depending on dose–weight group) and it prevented 50% or more reinfections for 29.4 days (range 16.4–48.8 days; Fig. 2c). Lumefantrine was estimated to provide over 90% protection for 12.1 days (range 9.0–20.6 days) and over 50% protection for 13.8 days (range 10.2–22.8 days; Fig. 2d). The duration of protection provided by both drugs varied by bodyweight, dose and age, but was particularly variable for piperaquine, in line with variable efficacy results by dose group18. The data on reinfection covered 42 days after treatment, while piperaquine was estimated to give some protection after 42 days in weight groups who have higher piperaquine exposures (Fig. 2c,e). However, in these age groups, the curves after 42 days are informed by dose–weight groups in whom piperaquine concentrations decline more quickly, reaching low levels within 42 days. We extended pharmacokinetic simulations of piperaquine and lumefantrine concentrations to all age groups using published age–weight relationships, and pharmacokinetic studies in adults, where available (Fig. 2e,f; Supplementary Methods; Supplementary Fig. 2).


Contrasting benefits of different artemisinin combination therapies as first-line malaria treatments using model-based cost-effectiveness analysis.

Okell LC, Cairns M, Griffin JT, Ferguson NM, Tarning J, Jagoe G, Hugo P, Baker M, D'Alessandro U, Bousema T, Ubben D, Ghani AC - Nat Commun (2014)

PKPD results.Concentration-effect curves for piperaquine (a) and lumefantrine (b) estimated from model fitting, with 95% CI. Piperaquine concentrations relate to capillary measurements and lumefantrine concentrations to venous measurements. Probability of protection from reinfection over time since the first dose based on pharmacokinetic models: piperaquine (c,e) and lumefantrine (d,f), simulations in children <10 years in the clinical trials (c,d) and in all age–weight groups based on Tanzanian bodyweight distribution (e,f). Probability of protection from reinfection over time since the first dose with piperaquine (g) or lumefantrine (h)—model fits and 95% CI using a Weibull survival function instead of pharmacokinetic models.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263185&req=5

f2: PKPD results.Concentration-effect curves for piperaquine (a) and lumefantrine (b) estimated from model fitting, with 95% CI. Piperaquine concentrations relate to capillary measurements and lumefantrine concentrations to venous measurements. Probability of protection from reinfection over time since the first dose based on pharmacokinetic models: piperaquine (c,e) and lumefantrine (d,f), simulations in children <10 years in the clinical trials (c,d) and in all age–weight groups based on Tanzanian bodyweight distribution (e,f). Probability of protection from reinfection over time since the first dose with piperaquine (g) or lumefantrine (h)—model fits and 95% CI using a Weibull survival function instead of pharmacokinetic models.
Mentions: The cumulative rate of PCR-confirmed reinfection in the clinical trial data was generally higher in children treated with AL compared with DHA–PQP (Fig. 1), with the difference tending to be larger in higher transmission sites due to more reinfection events. The best-fitting model predictions from our PKPD model were within the 95% confidence intervals (CI) of the large majority of data points (Fig. 1). The concentration at which each antimalarial prevents 50% of new infections from successfully establishing as blood-stage infections was estimated at 22.1 ng ml−1 for piperaquine and 332.3 ng ml−1 for lumefantrine (Fig. 2a,b; Table 1). In the study populations in which the clinical trials were conducted, the mean number of days for which piperaquine prevented 90% or more reinfections was 26.2 (range 13.6–45.0 days depending on dose–weight group) and it prevented 50% or more reinfections for 29.4 days (range 16.4–48.8 days; Fig. 2c). Lumefantrine was estimated to provide over 90% protection for 12.1 days (range 9.0–20.6 days) and over 50% protection for 13.8 days (range 10.2–22.8 days; Fig. 2d). The duration of protection provided by both drugs varied by bodyweight, dose and age, but was particularly variable for piperaquine, in line with variable efficacy results by dose group18. The data on reinfection covered 42 days after treatment, while piperaquine was estimated to give some protection after 42 days in weight groups who have higher piperaquine exposures (Fig. 2c,e). However, in these age groups, the curves after 42 days are informed by dose–weight groups in whom piperaquine concentrations decline more quickly, reaching low levels within 42 days. We extended pharmacokinetic simulations of piperaquine and lumefantrine concentrations to all age groups using published age–weight relationships, and pharmacokinetic studies in adults, where available (Fig. 2e,f; Supplementary Methods; Supplementary Fig. 2).

Bottom Line: DHA-PQP has a modestly higher estimated impact than AL in 64% of the population at risk.Given current higher cost estimates for DHA-PQP, there is a slightly greater cost per case averted, except in areas with high, seasonally varying transmission where the impact is particularly large.We find that a locally optimized treatment policy can be highly cost effective for reducing clinical malaria burden.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College, London W2 1PG, UK.

ABSTRACT
There are currently several recommended drug regimens for uncomplicated falciparum malaria in Africa. Each has different properties that determine its impact on disease burden. Two major antimalarial policy options are artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PQP). Clinical trial data show that DHA-PQP provides longer protection against reinfection, while AL is better at reducing patient infectiousness. Here we incorporate pharmacokinetic-pharmacodynamic factors, transmission-reducing effects and cost into a mathematical model and simulate malaria transmission and treatment in Africa, using geographically explicit data on transmission intensity and seasonality, population density, treatment access and outpatient costs. DHA-PQP has a modestly higher estimated impact than AL in 64% of the population at risk. Given current higher cost estimates for DHA-PQP, there is a slightly greater cost per case averted, except in areas with high, seasonally varying transmission where the impact is particularly large. We find that a locally optimized treatment policy can be highly cost effective for reducing clinical malaria burden.

Show MeSH
Related in: MedlinePlus