Validade interna de ensaios terapêuticos em malária: análise de estudos de avaliação da emergência de resistência in vivo do Plasmodium vivax a doses padronizadas de primaquina

Abstract

Parasite resistance can be defined as the ability of a parasite strain to survive and/or to multiply despite the administration and absorption of a drug given in doses equal or higher than those usually recommended, but within the limits of tolerance of the patients. Therefore, the ideal study design to be used to monitor emergence of parasite resistance would use historical controls or any valid baseline data. Moreover, it is desirable to have some control of remaining determinants of therapeutic failure, not related to biological parasite resistance, which could vary over time and would have potential to distort the analysis for detecting emergence of parasite resistance. Here we comment on the internal validity of studies, which aim to assess the in vivo Plasmodium vivax emergence of resistance to standard doses of primaquine used routinely by health services. Few studies have paid attention to the need to control for other determinant factors of therapeutic failures or made any attempt to compare current findings with cure failure rates of historical controls from a given geographical area. Therefore, attention to the internal validity (and limitations) of study conclusions in these types of study is strongly advised.

Efficacy in the treatment of malaria by Plasmodium vivax in Oiapoque, Brazil, on the border with French Guiana: the importance of control over external factors

“…Studies in the Brazilian Amazon have reported decreased efficacy of these drugs for the treatment of P. vivax [ 10 , 12 , 15 , 35 , 36 ]. However, there are several difficulties to follows the standardized guidelines proposed by WHO for evaluation of the efficacy of anti-malarial drugs in Brazilian Amazon basin either by its continental dimensions or by the larger border with other Amazon countries with their own police of diagnosis and treatment of the disease [ 2 , 9 – 12 , 15 , 16 ]. These limitations impose methodological differences, such as the length of treatment, dose adjustments of primaquine as a function of patient weight, dose administered, and the no assessment of anti-malarial drugs exposure, hinder comparisons of studies of the therapeutic efficacy of the chloroquine and primaquine combination against P. vivax [ 2 , 9 – 12 , 15 , 16 ].…”

“…However, there are several difficulties to follows the standardized guidelines proposed by WHO for evaluation of the efficacy of anti-malarial drugs in Brazilian Amazon basin either by its continental dimensions or by the larger border with other Amazon countries with their own police of diagnosis and treatment of the disease [ 2 , 9 – 12 , 15 , 16 ]. These limitations impose methodological differences, such as the length of treatment, dose adjustments of primaquine as a function of patient weight, dose administered, and the no assessment of anti-malarial drugs exposure, hinder comparisons of studies of the therapeutic efficacy of the chloroquine and primaquine combination against P. vivax [ 2 , 9 – 12 , 15 , 16 ]. As an example, epidemiological records of the Malaria Epidemiological Surveillance Information System ( Sistema de Informação de Vigilância Epidemiológica —SIVEP-Malária)/MS in Oiapoque indicated that 14.2 and 13.5 % of cure verification slides were positive in 2009 and 2010, respectively.…”

“…Several studies have evaluated the efficacy of chloroquine plus primaquine for P. vivax in Brazil and in other countries of South America; however, the use of non-standardized protocols makes it difficult to compare the percentages of treatment failure [ 10 – 15 ]. Additionally, few studies have assessed in an integrated way the factors that are responsible for treatment failure but not directly related to resistance of the parasite or the host immune response [ 16 – 18 ]. Thus, this study aimed to evaluate the therapeutic and parasitological response of patients with vivax malaria treated with chloroquine and primaquine in the socio-environmental context of cross-border interactions between Brazil and French Guiana by considering adherence, concordance of diagnosis, primaquine dose adjustment for patient weight and quality of the anti-malarial drugs.…”

Subdoses of primaquine in overweight patients and malaria vivax relapses: report of two cases in the Federal District, Brazil

“…Numerous factors can interfere with the efficacy of antimalarial drugs, including certain factors related to the host (drug absorption, adherence to treatment, reinfection, immunity impairment, pharmacogenetic factors), the parasite (drug resistance), or even to correctly indicated treatment (deterioration of the drug quality, subtherapeutic doses) 1 . In both cases reported here, first-order factors were rejected due to the absence of clinical malabsorption indicators, such as diarrhea, vomiting and gastrointestinal alterations; lack of adherence was excluded, since administration of the drugs was supervised by Health Department staff; reinfection was unlikely to have occurred due to the permanence of patients after diagnostic confirmation within the Federal District, an area considered free from vectorial transmission; the patients did not present clinical evidence of immune impairment; though the possibility that pharmacogenetic factors might have contributed to the failure of standard dose treatment could not be excluded.…”

Deficiência de glicose-6-fosfato desidrogenase na resistência genética à malária: uma revisão sistemática e metanálise

“…A resistência à malária faz parte da interação de diferentes fatores reguladores da relação parasito-hospedeiro, como fatores genéticos (mutações e polimorfismos) e imunológicos, fazendo com que os indivíduos desenvolvam imunidade adquirida humoral ou celular (Yuthayong et al, 1993;Veronesi et al, 1999, SMITH et al, 2002Duarte et al, 2003;Nahrevanian, 2006;Coban et al, 2018). Polimorfismos genéticos são definidos quando ocorre uma mutação com frequência ≥ a 1% na população, sendo considerados importantes biomarcadores de gravidade de diversas patologias como cânceres, leishmaniose e tuberculose (Maulén et al, 2007;Motoori-Fernandes et al, 2019;Júnior et al, 2021).…”