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

ABSTRACT: 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.

SUBMITTER: Whegang Youdom S

PROVIDER: S-EPMC6380963 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Whegang Youdom Solange S Chiabi Andreas A Basco Leonardo K LK

Drugs in R&D 20190301 1

<h4>Introduction</h4>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.<h4>Methods</h4>A PubMed literature search was performed to analyse clinical trials conducted in Cameroon from 2001 to May 2017. Clinical studies that eva ...[more]

PMID: 30656608

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Project description:BackgroundNew antimalarial regimens, including artemisinin-based combination therapies (ACTs), have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials.Case descriptionBetween 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity.Discussion and evaluationDespite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported.ConclusionAlthough the World Health Organization has supported the development of pharmacovigilance systems in African countries deploying ACTs, additional guidance on adverse events monitoring in antimalarial clinical trials is needed, similar to the standardized recommendations available for assessment of drug efficacy.

Project description:BackgroundMalaria is a major cause of morbidity and mortality in pediatrics in malaria endemic areas. Artemisinin-based combination therapies (ACTs) are the drugs of choice for malaria management particularly across malaria-endemic countries. This systematic review and meta-analysis was performed to assess efficacy and safety of ACTs for uncomplicated malaria in pediatric populations.MethodsA body of evidence was searched for published ACT trials until March 06, 2020. The search was focused on efficacy and safety studies of ACTs for uncomplicated malaria in pediatrics. PubMed library was searched using best adapted search terms after multiple trials. References were exported to the endnote library and then to Covidence for screening. Data was extracted using the Covidence platform. The per-protocol analysis report for the efficacy and the intention-to-treat analysis for the safety were synthesized. Met-analysis was carried using Open Meta-Analyst software. Random effects model was applied and the heterogeneity of studies was evaluated using I2 statistic.ResultsNineteen studies were included in the final analysis. Overall, crude, PCR-corrected P. falciparum malaria treatment success rate was 96.3 and 93.9% for day 28 and 42, respectively. In the subgroup analysis, PCR-corrected adequate clinical and parasitological response (ACPR) of dihydroartemisinin-piperaquine (DP) was 99.6% (95% CI: 99.1 to 100%, I2 = 0%; 4 studies) at day 28 and 99.6% (95% CI of 99 to 100%, I2 = 0%; 3 studies) at day 42. Nine studies reported ACT related adverse drug reactions (ADR) (8.3%, 356/4304). The reported drug related adverse reactions ranged from 1.8% in DP (two studies) to 23.3% in artesunate-pyronaridine (AP). Gastrointestinal symptoms were the most common ACT related adverse effects, and all ADRs were reported to resolve spontaneously.ConclusionACTs demonstrated a high crude efficacy and tolerability against P. falciparum. The high treatment success and tolerability with low heterogeneity conferred by DP has implication for policy makers who plan the use of ACTs for uncomplicated falciparum malaria treatment in pediatrics.

Project description:IntroductionTriple artemisinin-based combination therapies (TACTs) are being developed as a response to artemisinin and partner drug resistance in the treatment of falciparum malaria in Southeast Asia. In African countries, where current artemisinin-based combination therapies (ACTs) are still effective, TACTs have the potential to benefit the larger community and future patients by mitigating the risk of drug resistance. This study explores the extent to which the antimalarial drug markets in African countries are ready for a transition to TACTs.MethodsA qualitative study was conducted in Nigeria and Burkina Faso and comprised in-depth interviews (n = 68) and focus group discussions (n = 11) with key actor groups in the innovation system of antimalarial therapies.ResultsEvidence of ACT failure in African countries and explicit support for TACTs by the World Health Organization (WHO) and international funders were perceived important determinants for the market prospects of TACTs in Nigeria and Burkina Faso. At the country level, slow regulatory and implementation procedures were identified as potential barriers towards rapid TACTs deployment. Integrating TACTs in public sector distribution channels was considered relatively straightforward. More challenges were expected for integrating TACTs in private sector distribution channels, which are characterized by patient demand and profit motives. Finally, several affordability and acceptability issues were raised for which ACTs were suggested as a benchmark.ConclusionThe market prospects of TACTs in Nigeria and Burkina Faso will depend on the demonstration of the added value of TACTs over ACTs, their advocacy by the WHO, the inclusion of TACTs in financial and regulatory arrangements, and their alignment with current distribution and deployment practices. Further clinical, health-economic and feasibility studies are required to inform decision makers about the broader implications of a transition to TACTs in African counties. The recent reporting of artemisinin resistance and ACT failure in Africa might change important determinants of the market readiness for TACTs.

Dataset Information

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

Publications

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

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