Graduation Year

2015

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Global Health

Major Professor

Ricardo Izurieta, M.D., Dr. P.H.

Committee Member

Jaime Corvin, Ph.D.

Committee Member

Mauricio Espinel, Ph.D.

Committee Member

Boo Kwa, Ph.D.

Committee Member

Wilbur Milhous, Ph.D.

Keywords

early malaria treatment, malaria transmission, malaria control, malaria elimination

Abstract

Malaria is a disease that causes great burden in public health worldwide. It was estimated that in 2011 there were 3.3 billion people at risk of acquiring malaria. According to data from the Ministry of Public Health of Ecuador, malaria incidence has shown a 99.9% steady decrease since year 2000. This study evaluated the effect of timely treatment on circulating gametocyte and malaria incidence rates. All cases reported in the province of Esmeraldas, Ecuador from July 2012 to March 2015 and to the national headquarters between February 2012 and December 2014 were studied. The effect of early treatment on: 1) follow-up gametocytemia at an individual level (cases reported in Esmeraldas); and, 2) incidence rates at a population level (within Esmeraldas and within Ecuador) was evaluated using a retrospective cohort and an ecologic study design, respectively.

A total of 193 cases from the province of Esmeraldas were included in the retrospective cohort study. Patients were classified into three groups depending on time to treatment (i.e. how many days elapsed from symptoms onset to treatment) as follows: 1) early treatment for those treated within 2 days; 2) late treatment for those treated between 3 to 7 days; and, 3) extremely late for those receiving treatment after 7 days. A consistent association between time to treatment and follow-up gametocytemia was found in different regression models including logistic (adjusted OR = 0.20 and 0.28 for early and late treatment, respectively, p < 0.05), linear (parameter estimate = 0.018, p < 0.05) Poisson log linear (parameter estimate 0.103, p < 0.05), and negative binomial (parameter estimate = 0.111, p < 0.05). Extremely late patients had higher follow-up gametocytemia levels during follow-up visits 1 and 2. A survival analysis showed that extremely late treated patients tend to clear gametocytes later than the other two treatment arms (p > 0.05). Finally, there was a positive association between time to treatment and a period of transmisibiltiy, which was estimated based on the potential number of days that a patient has gametocytemia (p < 0.05).

Population-level associations between time to treatment and malaria incidence rates were assessed through a two-tiered ecologic study: nationwide for Ecuador and provincewide for Esmeraldas.. A parish-level anlaysis of malaria among all parishes in the province of Esmeraldas revealed that malaria transmission differs widely within each population-level treatment arm classification group. A repeated measures negative binomial regression showed that there is a positive association between malaria incidence rate in subsequent periods and mean time to treatment, follow-up gametocytemia and a negative association with malaria incidence rate in the previous period (p < 0.05 for all associations). The nationwide analysis confirmed that there is wide variation in malaria incidence rate within each population-level treatment arm classification group.

Although the World Health Organization (WHO) recommends timely malaria treatment there seems to be lack of peer-reviewed published evidence evaluating the association of time to malaria treatment with follow-up gametocytemia and incidence rates, especially in Latin America. This study has important public health implications. Firstly, there seems to be no clear definition for early malaria treatment. In this study, consistent evidence of the association between time to treatment and, specifically, early malaria treatment (i.e. malaria within 2 days of symptoms onset) with follow-up gametocytemia and period of transmissibliity is provided. Evidence provided here can serve as a basis for future research in other countreis facing similar conditions. Additionally, this information can serve to better inform public health policy, especially regarding the definition of early treatment and, thus, setting goals to accomplish early treatment among malaria infected patients. Noteworthy, Esmeraldas and Ecuador face significant challenges not only to achieve but to maintain malaria elimination, if achieved. These challenges arise from favorable local environmental conditions and to certain vulnerabilities like proximity to neibhoring areas with high malaria incidence, susceptibility to receive migration, specially refugees fleeing armed conflict, socio-economic disadvantages and remoteness of some parishes were malaria remains active. Moreover, the integration of the current national malaria control program into the organizational strucutre of the Ministry of Health may impose additional challenges like: 1) differential prioritization of other diseases, 2) lack of clear guidance about the role of the current malaria-dedicated personnel in the MoH strucutre; and, 3) lack of specification about on whom would accountability for malaria control rely. All these vulnerabilities should be properly addressed if malaria elimination is to be achieved in Ecuador. Finally, further research is required to confirm whether these trends and association are replicable across different populations, countries and continents. If these associations are similar or even stronger in other populations, then better malaria control programs informed in evidence-based definition of early malaria treatment could certainly be planned and implemented to achieve malaria elimination and control in other regions of the world.

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