Decreasing Efficacy of Antimalarial Combination Therapy in Uganda Is Explained by Decreasing Host Immunity Rather than Increasing Drug Resistance

Greenhouse, Bryan; Slater, Madeline; Njama-Meya, Denise; Nzarubara, Bridget; Maiteki‐Sebuguzi, Catherine; Clark, Tamara D.; Staedke, Sarah G.; Kamya, Moses R.; Hubbard, Alan; Rosenthal, Philip J.; Dorsey, Grant

doi:10.1086/596741

Cited by 30 publications

(39 citation statements)

References 48 publications

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“…It has long been known that increasing failure rates of other drugs can be due to decreased immunity rather than increased resistance. For example, Greenhouse and colleagues (37) concluded that the increasing drug failure rates in their longitudinal study were due to decreasing levels of immunity rather than changes in parasites drug resistance levels. Similarly, LoperaMesa et al (38) reported that clearance rates at their study sites most likely reflected differences in patients' immune status.…”

Section: Discussionmentioning

confidence: 99%

How Robust Are Malaria Parasite Clearance Rates as Indicators of Drug Effectiveness and Resistance?

Hastings

Kay

Hodel

2015

Antimicrob Agents Chemother

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Artemisinin-based combination therapies (ACTs) are currently the first-line drugs for treating uncomplicated falciparum malaria, the most deadly of the human malarias. Malaria parasite clearance rates estimated from patients' blood following ACT treatment have been widely adopted as a measure of drug effectiveness and as surveillance tools for detecting the presence of potential artemisinin resistance. This metric has not been investigated in detail, nor have its properties or potential shortcomings been identified. Herein, the pharmacology of drug treatment, parasite biology, and human immunity are combined to investigate the dynamics of parasite clearance following ACT. This approach parsimoniously recovers the principal clinical features and dynamics of clearance. Human immunity is the primary determinant of clearance rates, unless or until artemisinin killing has fallen to near-ineffective levels. Clearance rates are therefore highly insensitive metrics for surveillance that may lead to overconfidence, as even quite substantial reductions in drug sensitivity may not be detected as lower clearance rates. Equally serious is the use of clearance rates to quantify the impact of ACT regimen changes, as this strategy will plausibly miss even very substantial increases in drug effectiveness. In particular, the malaria community may be missing the opportunity to dramatically increase ACT effectiveness through regimen changes, particularly through a switch to twice-daily regimens and/or increases in artemisinin dosing levels. The malaria community therefore appears overreliant on a single metric of drug effectiveness, the parasite clearance rate, that has significant and serious shortcomings.T he timely provision of effective antimalarial drugs is a public health priority in most of the developing world (1). The current generation of antimalarial drugs centers on artemisininbased combination therapies (ACTs), and recent reports that tolerance of and/or resistance to artemisinins is evolving (2-7) have caused considerable concern (8-12). ACTs remain largely effective in clearing malaria infections, but reduced parasite clearance rates (i.e., the rate at which parasitemia declines after treatment [13]) have been widely interpreted as indicating the presence of reduced parasite sensitivity to the artemisinin component and hence indicative of the early stages of resistance (2-12). Parasite clearance rates have also been used to evaluate the likely clinical impact of alterations in artemisinin or ACT dosing regimens (14) that may be able to increase ACT effectiveness and hence reduce the threat of resistance. It therefore seems reasonable to expect that parasite clearance rates are a well-validated, demonstrably robust measure of drug effectiveness and resistance. Unfortunately, this appears not to be the case, as reflected in concerns raised in recent commentaries (15-17). Herein, the pharmacology of drug action, parasite biology, and human immunity are combined to investigate the dynamics of parasite clearance following...

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Section: Discussionmentioning

confidence: 99%

How Robust Are Malaria Parasite Clearance Rates as Indicators of Drug Effectiveness and Resistance?

Hastings

Kay

Hodel

2015

Antimicrob Agents Chemother

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“…The rapid spread of CQ and SP resistance may be due to some degree to high gametocyte carriage after treatment and treatment failure (26).These associations are explained only partly by ongoing gametocyte production by asexual parasites that survive the failing antimalarial treatment. Not all genetically resistant parasites will result in treatment failure, which depends on parasite sensitivity, drug concentration, and host immunity (116,142,175,474). Even if resistant parasites are cleared successfully, they appear to have a transmission advantage over fully sensitive (wild-type) parasite strains.…”

Section: Gametocytes As An Early Marker For Spread Of Drug Resistancementioning

confidence: 99%

Epidemiology and Infectivity of Plasmodium falciparum and Plasmodium vivax Gametocytes in Relation to Malaria Control and Elimination

2011

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SUMMARY Malaria remains a major cause of morbidity and mortality in the tropics, with Plasmodium falciparum responsible for the majority of the disease burden and P. vivax being the geographically most widely distributed cause of malaria. Gametocytes are the sexual-stage parasites that infect Anopheles mosquitoes and mediate the onward transmission of the disease. Gametocytes are poorly studied despite this crucial role, but with a recent resurgence of interest in malaria elimination, the study of gametocytes is in vogue. This review highlights the current state of knowledge with regard to the development and longevity of P. falciparum and P. vivax gametocytes in the human host and the factors influencing their distribution within endemic populations. The evidence for immune responses, antimalarial drugs, and drug resistance influencing infectiousness to mosquitoes is reviewed. We discuss how the application of molecular techniques has led to the identification of submicroscopic gametocyte carriage and to a reassessment of the human infectious reservoir. These components are drawn together to show how control measures that aim to reduce malaria transmission, such as mass drug administration and a transmission-blocking vaccine, might better be deployed.

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“…Malarial incidence was heterogeneous, and associated with host genetics, use of bednets, and distance of a child's residence from a mosquito breeding site [19]. The efficacy of AQ/SP diminished over time, but this change appeared to be due to changes in host immunity rather than increasing parasite resistance to the components of AQ/SP [20]. We now present a final evaluation of the relative efficacies of the 3 combination antimalarial therapies, changes in the prevalence of malarial parasitemia and incidence of malaria over time, and other clinical features in this urban cohort of Ugandan children.…”

Section: Introductionmentioning

confidence: 99%

Incidence of Malaria and Efficacy of Combination Antimalarial Therapies over 4 Years in an Urban Cohort of Ugandan Children

et al. 2010

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BackgroundCombination therapies are now recommended to treat uncomplicated malaria. We used a longitudinal design to assess the incidence of malaria and compare the efficacies of 3 combination regimens in Kampala, Uganda.Methodology/Principal FindingsChildren aged 1–10 years were enrolled from randomly selected households in 2004–05 and 2007, and were followed at least monthly through 2008. Insecticide-treated bednets (ITNs) were provided in 2006. Children were randomized upon their first episode, and then treated for all episodes of uncomplicated malaria with amodiaquine/sulfadoxine-pyrimethamine (AQ/SP), artesunate/amodiaquine (AS/AQ), or artemether/lumefantrine (AL). Risks of parasitological failure were determined for each episode of uncomplicated malaria and clinical parameters were followed. A total of 690 children experienced 1464 episodes of malaria. 96% of these episodes were uncomplicated malaria and treated with study drugs; 94% were due to Plasmodium falciparum. The rank order of treatment efficacy was AL > AS/AQ > AQ/SP. Failure rates increased over time for AQ/SP, but not the artemisinin-based regimens. Over the 4-year course of the study the prevalence of asymptomatic parasitemia decreased from 11.8% to 1.4%, the incidence of malaria decreased from 1.55 to 0.32 per person year, and the prevalence of anemia (hemoglobin <10 gm/dL) decreased from 5.9% to 1.0%. No episodes of severe malaria (based on WHO criteria) and no deaths were seen.Conclusions/SignificanceWith ready access to combination therapies and distribution of ITNs, responses were excellent for artemisinin-containing regimens, severe malaria was not seen, and the incidence of malaria and prevalence of parasitemia and anemia decreased steadily over time.Trial Registrationisrctn.org ISRCTN37517549

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Decreasing Efficacy of Antimalarial Combination Therapy in Uganda Is Explained by Decreasing Host Immunity Rather than Increasing Drug Resistance

Cited by 30 publications

References 48 publications

How Robust Are Malaria Parasite Clearance Rates as Indicators of Drug Effectiveness and Resistance?

How Robust Are Malaria Parasite Clearance Rates as Indicators of Drug Effectiveness and Resistance?

Epidemiology and Infectivity of Plasmodium falciparum and Plasmodium vivax Gametocytes in Relation to Malaria Control and Elimination

Incidence of Malaria and Efficacy of Combination Antimalarial Therapies over 4 Years in an Urban Cohort of Ugandan Children

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