Anti-malarial drugs exposure in endemic areas of malaria and COVID-19

Malaria is an important health issue in the Region of the Americas, with approximately 138 million individuals in 19 countries at risk to contract the disease in 2018.  Most of the cases occurred in Brazil, Colombia, and Venezuela, which accounted for 80% of the estimated cases. In Brazil, most cases occurred in the Amazon basin (99%), where the pattern of distribution of the disease is heterogeneous and Plasmodium vivax accounted for 85-90% of cases. The state of Para is localized in the eastern portion of the Brazilian Amazon basin, has an estimate population of 8,5 million of individuals and reported in the last two years a significant decrease in the of cases of malaria from 40043 in 2018 to 27916 in 2019, due to the strength the efforts to control the mosquito vector and the early and adequate treatment of the cases. Recently, the state of Para suffered the impact of Coronavirus disease (COVID-19), with approximately 101,000 cases officially reported and 5000 deaths. In this scenario, the coexistence of COVID-19 and malaria is a matter of interest, and the WHO launched a document on the imminent negative impact of COVID-19 pandemic in the fight against malaria highlighting issues related to the detection and diagnosis of the cases, treatment, and the routine control vectors. Therefore, three dimensions can be considered: the patient behavior, the response of the health system, and the availability of chloroquine to treat P. vivax cases.   Another relevant issue was the widespread use of chloroquine and hydroxychloroquine to treat COVID-19 in the State of Para, which could impact the P. vivax malaria treatment outcomes, increasing the time for clearance of parasites as well as the presence of residual concentrations of the anti-malarial drugs. Therefore, the aims of the present study were to assess the epidemiological profile of patients with COVID-19 from an endemic area of the Brazilian Amazon basin and to estimate aspects of the exposure to anti-malarial drugs and the hematological changes in patients with P. vivax malaria with history of exposure to SARS-CoV-2. An observational study of cases will be performed in the meso-region of Marajo Island in the eastern portion of the Amazon basin. The epidemiological profile of patients with COVID-19 and the cases of malaria will be obtained from the public databases of the Secretary of Health of the State of Para. Two groups of patients will be formed: a) with malaria by P. vivax and history of COVID-19; b) with malaria by P. vivax and negative immunological test for COVID-19 in the last 60 days. Serial blood samples will be performed at admission on the study and on 1,3,5,7,14,21 and 28 after anti-malarial drug intake. Pharmacokinetics parameters will be obtained by non-compartmental modeling. Hematological parameters will be determined at each blood sampling. A parasite count will be performed each 12 hours until three consecutive negative slides. The follow-up will be of 42 days. The following questions will be answered in the study: 1) Which is the epidemiological profile of patients with COVID-19 from an endemic area of malaria. 2) Which the response of individuals from an endemic area for malaria facing COVID-19. 3) There are residual concentrations of chloroquine and desethylchloroquine in the study area? 4) the widespread use of chloroquine changed the plasma concentrations X parasite count curve. 5)  there was any change in the follow-up or in the time for parasite clearance in patients living in an endemic area with the widespread use of chloroquine and hydroxychloroquine? There are significant hematological differences in the study groups?     

Design

This is an observational  study of cases of patients with P. vivax malaria that were previously infected by SARS-CoV-2. 

Setting

The study will be performed in the region of the Marajo island in the State of Para. The meso-region of Marajo island has an extent of 40,100 Km2, and is divided in three microregions: 1) Arari with seven municipalities (Cachoeira do Arari, Chaves, Muana, Ponta de Pedras, Salvaterra, Santa Cruz do Arari and Soure); 2) Breves with five municipalities (Afua, Anajas, Breves, Curralinho and São Sebastião da Boa Vista); 3) Portel with 4 municipalities (Bagre, Gurupá, Melgaço and Portel). 

Methodology

For the epidemiological study the data were searched in open access health public sites of the Ministry of Health of Brazil and from the Secretary of Health of the State of Para. The cases of malaria were recorded from Jan 2018 to Jun 2018, Jan 2019 to Jun 2019, and from Jan 2020 to Jun 2020. The cases of coronavirus disease-2019 were recorded from Jan 2020 to June 2020.  For the evaluation of the residual concentrations of chloroquine and hydroxychloroquine, blood samples will be taken from patients with a slide confirmed infection by P. vivax before the use of anti-malarial drugs. To assess chloroquine exposure, two groups of ´patients will be formed, one with previous reports of COVID-19 and another with no diagnosis of the disease, blood samples will be collected at admission on the study and them on days 1,3, 7,14 21 and 28. The concentrations of chloroquine and desethylcholoroquine will be measured by High-performance liquid chromatography with fluorescence detection. A non-compartmental approach will be used to estimate the maximum concentration, the area under the curve, and the half-life. Parasite count will be performed each 12 hours to estimate the time for parasite clearance. Then, the profile of plasma concentration X parasite count will be determined. The data will be compared between the two groups .   

Outcome Measures

1. Epidemiological profile of patients with COVID-19 in an endemic area of P. vivax  malaria.
2. P. vivax malaria patient behavior facing covid-19 , assessed by the passive detection of cases and the time between appearance of signs and symptoms and the search for medical assitsance.                          
3. Health system response: measured by the active detection of cases and the number of patients followed by 42 days.
4. Number of patients with residual concentrations of chloroquine and desethylchloroqine
5. Pharmacokientics parameters of patients   with P. vivax  malaria with or without a history of COVID-19  
6. Time for parasite clearance of patients with P.vivax malaria form an endemic area with widespread use of chloroquine and hydroxychloroquine for treatment of  COVID-19.
7. Pharmacokinetics parameters of chloroquine in patients with P. vivax malaria   considering a history of COVID-19       

Drug-based Strategies
Measurement of Transmission
P. vivax

Jul 2020 — Dec 2023

Brazil

Clinical Epidemiology of COVID-19 in Malaria Settings