Methodological approaches for analysing data from therapeutic efficacy studies.

Several anti-malarial drugs have been evaluated in randomized clinical trials to treat acute uncomplicated Plasmodium falciparum malaria. The outcome of anti-malarial drug efficacy studies is classified into one of four possible outcomes defined by the World Health Organization: adequate clinical and parasitological response, late parasitological failure, late clinical failure, early treatment failure. These four ordered categories are ordinal data, which are reduced to either a binary outcome (i.e., treatment success and treatment failure) to calculate the proportions of treatment failure or to time-to-event outcome for Kaplan-Meier survival analysis. The arbitrary transition from 4-level ordered categories to 2-level type categories results in a loss of statistical power. In the opinion of the authors, this outcome can be considered as ordinal at a fixed endpoint or at longitudinal endpoints. Alternative statistical methods can be applied to 4-level ordinal categories of therapeutic response to optimize data exploitation. Furthermore, network meta-analysis is useful not only for direct comparison of drugs which were evaluated together in a randomized design, but also for indirect comparison of different artemisinin-based combinations across different clinical studies using a common drug comparator, with the aim to determine the ranking order of drug efficacy. Previous works conducted in Cameroonian children served as data source to illustrate the feasibility of these novel statistical approaches. Data analysis based on ordinal end-point may be helpful to gain further insight into anti-malarial drug efficacy.

Comparison of anti-malarial drugs efficacy in the treatment of uncomplicated malaria in African children and adults using network meta-analysis.

BACKGROUND: Artemisinin-based combination therapy (ACT) and novel drug combinations are available and used in African countries to treat uncomplicated malaria. Network meta-analysis methods are rarely and poorly applied for the comparison of their efficacies. This method was applied on a set of randomized controlled trials to illustrate its usefulness. METHODS: A literature review available in Pubmed was conducted in July 2016. Eligible studies, conducted in sub-Saharan Africa, published between 2002 and 2016, focused on randomized controlled trials of at least two artemisinin-based combinations to treat uncomplicated malaria in children and adults. Agglomerate data were: the number of PCR-corrected adequate clinical and parasitological response (ACPR) on day 28, used as the primary enDHAPoint in all interventions, the number of participants and the list of treatments. A Bayesian random effect meta-analysis using a binary outcome was the method to compare the efficacy. Ranking measure was used to obtain a hierarchy of the competing interventions. RESULTS: In total, 76 articles were included; 13 treatment regimens were involved and tested in 36,001 patients. Using artemether-lumefantrine (AL) as the common comparator for the entire network, 12 relative treatment effects were estimated and indirect comparisons were obtained. Dihydroartemisinin-piperaquine (DHAP) was shown to be more effective than AL (odds ratio [OR] = 1.92; 95% CI 1.30-2.82; 19,163 patients), ASAQ (OR = 1.70; 95% CI 1.10-2.64; 14,433 patients), and amodiaquine-sulfadoxine-pyrimethamine (AQSP): OR = 2.20; 95% CI 1.21-3.96; 8863 patients. Artesunate-amodiaquine (ASAQ) was comparable to AL (OR = 1.11; 95% CI 0.84-1.45; 21,235 patients). No significant difference was found between artesunate and mefloquine (ASMQ) and AL (OR = 1.20; 95% CI = 0.52-2.8; 13,824 participants). According to treatment ranking, among the WHO-recommended ACT medicines, DHAP was shown to be the most efficacious. CONCLUSIONS: Based on the available evidence, this study demonstrated the superiority of DHAP among currently recommended artemisinin-based combinations. The application of the methods described here may be helpful to gain better understanding of treatment efficacy and improve future decisions. However, more data are needed to allow robust conclusions about the results in comparison with novel drugs. Further surveillance of the efficacy of anti-malarial drugs and clinical trials are needed to closely follow the evolution of the epidemiology of drug-resistant malaria in Africa.

Randomized trial of artesunate-amodiaquine, atovaquone-proguanil, and artesunate-atovaquone-proguanil for the treatment of uncomplicated falciparum malaria in children.

BACKGROUND: Artemisinin-based combination therapies (ACTs) are recommended for the treatment of acute uncomplicated falciparum malaria in many malaria-endemic countries. Despite the emergence of artemisinin resistance, few alternative non-ACTs, including atovaquone-proguanil, are currently available. METHODS: Plasmodium falciparum-infected Cameroonian children ≤5 years old (n = 338) were randomly assigned to artesunate-amodiaquine, atovaquone-proguanil, or artesunate-atovaquone-proguanil treatment groups and followed for 28 days, according to the standard World Health Organization protocol. In vitro response to atovaquone and cytochrome b sequence of clinical isolates were determined. RESULTS: Eight late failures and 16 failures (8 late and 8 early failures) were observed after artesunate-amodiaquine and atovaquone-proguanil therapies, respectively. Most late failures were due to reinfections. Artesunate-atovaquone-proguanil was not associated with any failure. After correction by genotyping, per-protocol analysis showed no difference in the efficacy of 3 drugs. However, the proportion of atovaquone-proguanil-treated patients with positive smears on day 3 was much higher (36.0%; P < .05) than that of the artesunate-amodiaquine (2.9%) and artesunate-atovaquone-proguanil (1.0%) groups. In vitro response and cytochrome b sequence did not indicate atovaquone resistance. CONCLUSIONS: Atovaquone-proguanil was characterized by a slow blood schizontocidal action and resulted in early treatment failure in a few patients. Artesunate-atovaquone-proguanil was a highly effective alternative treatment. CLINICAL TRIALS REGISTRATION: UMIN000003813.

Midlife dietary vitamin D intake and subsequent performance in different cognitive domains.

BACKGROUND/AIMS: We evaluated the cross-time association between midlife dietary vitamin D intake and subsequent cognitive performance in a French general-population sample. METHODS: Data from participants in both the SU.VI.MAX trial (1994-2002) and the SU.VI.MAX 2 observational study (2007-2009) were used. Dietary intake was estimated at baseline from 6 or more 24-hour records. Cognitive performance was evaluated 13 years later with a comprehensive neuropsychological battery. Parameter estimates of cognitive performance according to quartiles (Q) of vitamin D intake were estimated via ANCOVA. RESULTS: In a sample of 1,990 aging adults, principal component analyses yielded two cognitive factors - for episodic/semantic memory and short-term memory/executive function; however, neither one displayed associations with dietary vitamin D intake. Midlife vitamin D intake was significantly and positively associated with scores on the forward digit span task measuring short-term memory (fully adjusted model: mean difference, Q4 vs. Q1 = 1.95; 95% CI 0.37-3.53; p(trend) = 0.03). No significant interaction with either sex or lifetime sun exposure was found. CONCLUSIONS: Midlife vitamin D intake exhibited a cross-time and domain-specific association with cognition in the context of aging. Further investigations in this area of prevention are warranted given the rapidly expanding elderly population and the absence of curative treatment for dementia.

Timeliness and missed opportunities for vaccination among children aged 0 to 23 months in Dschang health district, West region, Cameroon: A cross-sectional survey.

Missed opportunities for vaccination (MOV) reflect quality of immunization service. The objective of this study was to assess vaccination timeliness, prevalence, and characteristics of MOVs among children aged 0-23 months, as well as knowledge, attitude and practice of health workers towards immunization. An exit interview method was used to select caregivers and health personnel. Selection took place in 26 health facilities within 14 health areas in the Dshcang Health district. Data were collected using two face-to-face questionnaires adapted from the World Health Organization (WHO) tools. We conducted an evaluation of all free vaccines in the Expanded Programme on Immunisation (EPI). We studied timeliness, assessed MOV, and knowledge, behaviour and attitude of health workers on immunization. Basic statistical tests were used to study the association between MOV and socio demographic characteristics. A total of 363 children aged 0 to 23 months were surveyed. A total of 88 (91.66%) of health personnel agreed to participate in our study. A total of 298 (82.1%) children had vaccination cards with dates, leading to 18% not completely vaccinated. Vaccination timeliness ranged from 20% to 77%. Overall MOV estimated was 23.83%, range from 0% to 16.4% among all vaccines. Among health workers, 70.45% (62/88) had insufficient knowledge on vaccination, 73.86% assessed the vaccination status of children during any routine visit and 74% ask parents to bring the child's vaccination record to any health facility visit. The study highlighted presence of MOV among children. Strategies for remedying this includes strengthening parents' knowledge, organizing refresher courses for health workers on vaccination, and systematically assessing children's vaccination status.

Multiple treatment comparisons in a series of anti-malarial trials with an ordinal primary outcome and repeated treatment evaluations.

BACKGROUND: Artemisinin-based combination therapies (ACT) are widely used in African countries, including Cameroon. Between 2005 and 2007, five randomized studies comparing different treatment arms among artesunate-amodiaquine and other ACT were conducted in Cameroonian children aged two to 60 months who had uncomplicated Plasmodium falciparum malaria. In these studies, the categorical criterion proposed by the World Health Organization (WHO) to assess the relative effectiveness of anti-malarial drugs was repeatedly evaluated on Days 14, 21 and 28 after treatment initiation. The aim of the present study was to compare the effects of different treatments on this repeated ordinal outcome, hence using the fully available information. METHODS: The quantitative synthesis was based on individual patient data. Due to the incomplete block design concerning treatment arms between different trials, a mixed treatment comparison (MTC) meta-analysis approach was adopted. The repeated ordinal outcome was modelled through a latent variable, as a proportional odds mixed model with trial, period and treatment arms as covariates. The model was further complexified to account for the variance heterogeneity, and the individual log-residual variance was modelled as a linear mixed model, as well. The effects of individual covariates at inclusion, such as parasitaemia, fever, gender and weight, were also tested. Model parameters were estimated using a Bayesian approach via the WinBUGS software. After selecting the best model using Deviance Information Criterion (DIC), mixed treatment comparisons were based on the estimated treatment effects. RESULTS: Modeling the residual variance improved the model ability to adjust the data. The results showed that, compared to artesunate-amodiaquine (ASAQ), dihydroartemisinin-piperaquine (DHPP) was significantly more efficacious. Artesunate-chlorproguanil-dapsone (ASCD) was less efficacious than artesunate-sulphadoxine-pyrimethamine (ASSP), artemether-lumefantrine (AMLM) and DHPP, the difference with the latter being significant. No difference in efficacy was found between ASAQ and AMLM. CONCLUSIONS: Bayesian mixed treatment comparisons of a network of connected randomized trials with repeated measurements of the primary categorical outcome allowed to take into account both the individual- and between- studies sources of heterogeneity. The results of the present study complete the previous quantitative review based on a binary outcome at a fixed time point, suggesting that DHPP represents an alternative for the treatment of uncomplicated P. falciparum malaria in Cameroonian children.

Modelling and projections of the COVID-19 epidemic and the potential impact of social distancing in Cameroon.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) pandemic continues to be a global health problem with a significant impact in Cameroon. The aim of this study was to improve the understanding of the spread of COVID-19 and enhance disease control strategies. We assessed the SIRD (susceptible, infected, recovered and death) model to describe COVID-19 reported cases in Cameroon from March 7 to May 31, 2020, and study the impact of social distancing. We assessed changes in the basic reproduction number (R0) on a phaseadjusted process and forecasted the longterm epidemic trend. Daily incidence data was fitted to a log-linear model before each peak of the epidemic with the purpose of studying the effective mechanism of variation of the reproduction number Re. Before the first peak of the epidemic, R0 was estimated as 6.8. Social distancing and restricted measures contributed to reduce the value to 3.24 by April 30 but remained greater than 1 (R0=2.43) by May 22 when the initial measures implemented by the government to control the spread of the disease were relaxed. The estimated number of infections ranged 13,703-18,456 by May 31, and will continue increasing throughout June 2020 with more than 20,000 cases expected by the end of June 2020, suggesting that the pandemic is still in the growth phase. Longterm prediction showed a flattened curve towards April 2021. Preventive measures initially implemented by the government of Cameroon should be strictly maintained and reinforced to reduce Re to 0.5.

Monitoring the Efficacy and Safety of Artemisinin-Based Combination Therapies: A Review and Network Meta-analysis of Antimalarial Therapeutic Efficacy Trials in Cameroon.

INTRODUCTION: Artemisinin-based combination therapies (ACTs) are the first-line antimalarial drugs used to treat uncomplicated Plasmodium falciparum alaria in many endemic countries worldwide. The present work reviewed the therapeutic efficacy of ACT in Cameroon more than 10 years after the initial change in national drug policy in 2004. METHODS: A PubMed literature search was performed to analyse clinical trials conducted in Cameroon from 2001 to May 2017. Clinical studies that evaluated ACT for the treatment of uncomplicated falciparum malaria in children or adults, and reported efficacy and/or safety, were included. In addition, a small network meta-analysis (NMA) with a frequentist approach was performed. RESULTS: Six papers were selected from 48 articles screened and were full-text reviewed. The efficacy of both artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) ranged from moderate to high, with polymerase chain reaction-corrected cure rates ranging from 96.7 to 100% and 88.2 to 100%, respectively, in per-protocol analysis, and 86.2 to 96.7% and 74.0 to 90.6%, respectively, in intention-to-treat analysis. The malaria evidence network suggested that AL and ASAQ efficacies were comparable. The highest day 3 parasite positivity rate was 8.2% for ASAQ and 4% for AL. A novel ACT, artesunate-atovaquoneproguanil (ASATPG) was tested once and showed a cure rate of 100%. Based on an ITT approach, the NMA revealed that AL was more efficacious than ASAQ, but the difference was not statistical significant (706 participants, three randomised clinical trials (RCT); OR 1.25, 95%CI 0.78-2.00). Adverse events ranged from mild to moderate severity but were not directly attributed to drug intake. CONCLUSION: ACTs are still effective and safe in Cameroon; however, there are insufficient data on their efficacy, safety and tolerability, therefore more RCTs should be conducted, including novel ACTs.