Statistical methods to derive efficacy estimates of anti-malarials for uncomplicated Plasmodium falciparum malaria: pitfalls and challenges

Dahal, Prabin; Simpson, Julie A.; Dorsey, Grant; Guérin, Philippe J; Price, Ric N.; Stepniewska, Kasia

doi:10.1186/s12936-017-2074-7

Cited by 14 publications

(15 citation statements)

References 43 publications

(64 reference statements)

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“…In South America, P. vivax remains a hurdle in the eradication of malaria because of its ability to relapse from latent hypnozoites [ 8 ]. Differentiating re-infection from relapse is difficult [ 9 , 10 ]. In French Guiana, relapses are distinguished using the 90-day rule, which states that after a first vivax malaria episode, any vivax episode occurring within 90 days is considered a relapse, whereas those occurring after 90 days are re-infections [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Primaquine 30 mg/day versus 15 mg/day during 14 days for the prevention of Plasmodium vivax relapses in adults in French Guiana: a historical comparison

Valdés

Epelboin

Mosnier

et al. 2018

Malar J

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BackgroundThe preventive treatment of Plasmodium vivax relapse recommended by the World Health Organization is primaquine at a dose of 15 mg/day for 14 days, except for malaria cases from Asia and Oceania. Since 2006, CDC recommends the use of primaquine at 30 mg/day for 14 days. In France, all cases of malaria due to P. vivax are treated with 30 mg of primaquine. This systematically increased dosage needs to be evaluated according to epidemiological context. The aim of the study was to compare relapses after 14 days of primaquine at 15 or 30 mg/day.MethodsAll patients treated with primaquine after a vivax malaria episode in French Guiana, between 1 January, 2007 and 1 August, 2016, were studied. Based on the compulsory hospital pharmacy forms for primaquine delivery, adult patients who received 15 or 30 mg of primaquine during 14 days for hypnozoite eradication were included. The recommended dose was initially 15 mg and was changed to 30 mg in 2011. Vivax malaria recurrences within 2 months after primaquine treatment, and vivax malaria recurrences 2–6 months after primaquine in each treatment group were analysed using survival analysis at 2, 3 and 6 months.ResultsOut of 544 patients included, 283 received 15 mg/day and 261 received 30 mg/day of primaquine. At 2 and 3 months after primaquine treatment, the number of recurrences was 7 (2.5%) and 19 (7.3%), and 9 (3.4%) and 15 (5.3%), in the 15 and 30 mg groups (p = 0.51 respectively 0.35), respectively. Within 3 months, the median time to recurrence was 2.05 months in the 15 and 30 mg groups. At 6 months after primaquine treatment, the number of recurrences was 25 (8.8%) and 31 (11.9%) at 15 and 30 mg, respectively (p = 0.24). The median time to recurrence was 2.38 months at 15 mg/day and of 2.64 months at 30 mg/day.ConclusionsThere were no significant differences between primaquine at 15 or 30 mg/day for 14 days in the prevention of P. vivax relapses at 2, 3 and 6 months after primaquine treatment in French Guiana.

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Section: Introductionmentioning

confidence: 99%

Primaquine 30 mg/day versus 15 mg/day during 14 days for the prevention of Plasmodium vivax relapses in adults in French Guiana: a historical comparison

Valdés

Epelboin

Mosnier

et al. 2018

Malar J

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“…Clinical drug efficacy trials suffer from various complications, including non-compliance, protocol withdrawals and deviations (e.g., co-morbidity, exposure to new infections and health worker mistakes) that may result in participants being dropped during the analysis phase. The Intention-To-Treat analytical approach is advantageous because it includes all study participants according to the initial randomization, regardless of deviations from the protocol, such as participant withdrawals from the study or re-infection [59][60][61].…”

Section: Discussionmentioning

confidence: 99%

Global estimation of anti-malarial drug effectiveness for the treatment of uncomplicated Plasmodium falciparum malaria 1991–2019

Rathmes

Rumisha

Lucas

et al. 2020

Malar J

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Background Anti-malarial drugs play a critical role in reducing malaria morbidity and mortality, but their role is mediated by their effectiveness. Effectiveness is defined as the probability that an anti-malarial drug will successfully treat an individual infected with malaria parasites under routine health care delivery system. Anti-malarial drug effectiveness (AmE) is influenced by drug resistance, drug quality, health system quality, and patient adherence to drug use; its influence on malaria burden varies through space and time. Methods This study uses data from 232 efficacy trials comprised of 86,776 infected individuals to estimate the artemisinin-based and non-artemisinin-based AmE for treating falciparum malaria between 1991 and 2019. Bayesian spatiotemporal models were fitted and used to predict effectiveness at the pixel-level (5 km × 5 km). The median and interquartile ranges (IQR) of AmE are presented for all malaria-endemic countries. Results The global effectiveness of artemisinin-based drugs was 67.4% (IQR: 33.3–75.8), 70.1% (43.6–76.0) and 71.8% (46.9–76.4) for the 1991–2000, 2006–2010, and 2016–2019 periods, respectively. Countries in central Africa, a few in South America, and in the Asian region faced the challenge of lower effectiveness of artemisinin-based anti-malarials. However, improvements were seen after 2016, leaving only a few hotspots in Southeast Asia where resistance to artemisinin and partner drugs is currently problematic and in the central Africa where socio-demographic challenges limit effectiveness. The use of artemisinin-based combination therapy (ACT) with a competent partner drug and having multiple ACT as first-line treatment choice sustained high levels of effectiveness. High levels of access to healthcare, human resource capacity, education, and proximity to cities were associated with increased effectiveness. Effectiveness of non-artemisinin-based drugs was much lower than that of artemisinin-based with no improvement over time: 52.3% (17.9–74.9) for 1991–2000 and 55.5% (27.1–73.4) for 2011–2015. Overall, AmE for artemisinin-based and non-artemisinin-based drugs were, respectively, 29.6 and 36% below clinical efficacy as measured in anti-malarial drug trials. Conclusions This study provides evidence that health system performance, drug quality and patient adherence influence the effectiveness of anti-malarials used in treating uncomplicated falciparum malaria. These results provide guidance to countries’ treatment practises and are critical inputs for malaria prevalence and incidence models used to estimate national level malaria burden.

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“…Competing risk survival analysis is increasingly being used in the medical and statistical literature [8, 33]. However, this approach remains novel in the context of antimalarial research [34]. The K-M method is the currently recommended approach for deriving antimalarial drug efficacy of uncomplicated P. falciparum malaria.…”

Section: Discussionmentioning

confidence: 99%

Evaluating antimalarial efficacy in single-armed and comparative drug trials using competing risk survival analysis: a simulation study

Dahal

Guérin

Price

et al. 2019

BMC Med Res Methodol

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Background Antimalarial efficacy studies in patients with uncomplicated Plasmodium falciparum are confounded by a new infection (a competing risk event) since this event can potentially preclude a recrudescent event (primary endpoint of interest). The current WHO guidelines recommend censoring competing risk events when deriving antimalarial efficacy. We investigated the impact of considering a new infection as a competing risk event on the estimation of antimalarial efficacy in single-armed and comparative drug trials using two simulation studies. Methods The first simulation study explored differences in the estimates of treatment failure for areas of varying transmission intensities using the complement of the Kaplan-Meier (K-M) estimate and the Cumulative Incidence Function (CIF). The second simulation study extended this to a comparative drug efficacy trial for comparing the K-M curves using the log-rank test, and Gray’s k -sample test for comparing the equality of CIFs. Results The complement of the K-M approach produced larger estimates of cumulative treatment failure compared to the CIF method; the magnitude of which was correlated with the observed proportion of new infection and recrudescence. When the drug efficacy was 90%, the absolute overestimation in failure was 0.3% in areas of low transmission rising to 3.1% in the high transmission settings. In a scenario which is most likely to be observed in a comparative trial of antimalarials, where a new drug regimen is associated with an increased (or decreased) rate of recrudescences and new infections compared to an existing drug, the log-rank test was found to be more powerful to detect treatment differences compared to the Gray’s k -sample test. Conclusions The CIF approach should be considered for deriving estimates of antimalarial efficacy, in high transmission areas or for failing drugs. For comparative studies of antimalarial treatments, researchers need to select the statistical test that is best suited to whether the rate or cumulative risk of recrudescence is the outcome of interest, and consider the potential differing prophylactic periods of the antimalarials being compared. Electronic supplementary material The online version of this article (10.1186/s12874-019-0748-2) contains supplementary material, which is available to authorized users.

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Statistical methods to derive efficacy estimates of anti-malarials for uncomplicated Plasmodium falciparum malaria: pitfalls and challenges

Cited by 14 publications

References 43 publications

Primaquine 30 mg/day versus 15 mg/day during 14 days for the prevention of Plasmodium vivax relapses in adults in French Guiana: a historical comparison

Primaquine 30 mg/day versus 15 mg/day during 14 days for the prevention of Plasmodium vivax relapses in adults in French Guiana: a historical comparison

Global estimation of anti-malarial drug effectiveness for the treatment of uncomplicated Plasmodium falciparum malaria 1991–2019

Evaluating antimalarial efficacy in single-armed and comparative drug trials using competing risk survival analysis: a simulation study

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