Safety Of Artemisinin-based Combination Therapy Research Articles

Comparison of Efficacy and Safety of Artemisinin-Based Combination Therapies for Treating Uncomplicated Falciparum Malaria in Sub-Saharan African Countries: An Update on the Changes in Efficacy Using Network Meta-Analysis

Background: Several artemisinin-based combination therapies (ACT) are available to treat uncomplicated malaria in Africa. The present study aimed to assess the ranking of their efficacy and tolerance. Methods: A database of randomized controlled trials was retrieved from published papers. Network meta-analysis was used to compare efficacy on day 28 and day 42 after initiation of treatment. Age covariate effect on treatment outcome was assessed, and a modeling approach to reduce heterogeneity among trials was evaluated under the hypothesis of consistency in a meta-regression. Safety and adverse events were compared among different ACTs. A Bayesian analysis was performed to implement the consistency models using WinBUGS software. The results were compared to those of the frequentist approach using the R software. Results: Eighty-one articles, in which a total of 15 different ACTs were tested in more than 36,000 patients, were included. On day 28, dihydroartemisinin-piperaquine (DHPP) was more effective than artemether-lumefantrine (AL) before (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.31 - 2.56) and after age-covariate adjustment (OR, 1.70; 95% CI, 1.20 - 2.43). The result was similar on day 42. DHPP occupied the top rank. The risk of having cough, diarrhoea or headache post-treatment was significantly lower with DHPP than AL. Artesunate-mefloquine (ASMQ) was associated with a significantly lower prevalence of vomiting or nausea (OR, 0.80; 95% CI, 0.48 - 1.30) and headache (OR, 0.53; 95% CI, 0.40 - 0.68) compared to AL. On the contrary, vomiting and nausea occurred more frequently after fixed-dose artesunate-amodiaquine formulation (ASAQf) than with AL (OR, 1.45; 95% CI, 1.18 - 1.78). The risk of anaemia was higher with ASAQf and co-blistered artesunate-amodiaquine (ASAQc) than with AL. There was no significant difference in risk of anaemia (P > 0.05) between AL and different formulations of ASAQ. Conclusions: Based on the available evidence, this study demonstrated the superiority of DHPP, followed by AL, among currently recommended ACTs in terms of efficacy and tolerance. Network meta-analysis could be an alternative analytical tool but needs more data input from therapeutic efficacy studies. The determination of the best available therapy requires data triangulation and data science.

Efficacy and Safety of Artemisinin-Based Combination Therapy for the Treatment of Uncomplicated Malaria in Pregnant Women: A Systematic Review and Meta-Analysis.

IntroductionMalaria is one of the infectious diseases with substantial risks for pregnant women, the fetus and the newborn child. Thus, prevention and treatment of malaria with safe and effective drugs is of paramount importance. Pregnant women are mostly excluded from clinical trials, and systematic approaches of pharmacovigilance in pregnancy are limited. This means the safety and efficacy of antimalarial agents during pregnancy are unclear.PurposeThis study was designed to carry out a systematic review and aggregate data meta-analysis of literature published on efficacy and safety of artemisinin-based combination therapy (ACT) for uncomplicated malaria in pregnant women.MethodsA search of literature published between 1998 to 2020 on efficacy and safety of artemisinin-based combination therapy (ACT) in pregnant women was made using Cochrane Library, Medline and the Malaria in Pregnancy Consortium Library. Data were extracted independently by two reviewers, and any discrepancies were resolved by consensus. Meta-analysis was carried out using Open Meta-Analyst software. Random effects model was applied, and the heterogeneity of studies was evaluated using Higgins I2.ResultsTwenty-four studies that fulfilled the inclusion criteria were included in the final assessment. Overall, days 28 to 63 malaria treatment success rate was 96.1%. Overall days 28 to 63 cure rates for AL, AS+AQ, AS+MQ, DHA+PQ, AS+ATQ+PG and AS+SP were 95.1%, 92.2%, 97.0%,94.3%, 96.5% and 97.4%, respectively. Comparison of ACTs with non-ACTs revealed that the risk of treatment failure was substantially lower in patients treated with ACTs than with non-ACTs (risk ratio 0.20, 95% C.I. 0.09–0.43). The overall prevalences of miscarriage, stillbirth and congenital anomalies were 0.3%, 2.1% and 1.0%, respectively, and found to be comparable among various ACTs. There was comparable tolerability across ACTs during pregnancy.ConclusionACTs demonstrated a high cure rate, safety and tolerability against Plasmodium falciparum infection in pregnant women. The higher treatment success and comparable tolerability could be used as an input for decision makers to support the continued usage of ACTs for treatment of uncomplicated falciparum malaria in pregnant women.

Efficacy and safety of artemisinin-based combination therapies for the treatment of uncomplicated malaria in pediatrics: a systematic review and meta-analysis

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.

Efficacy and safety of artemisinin-based combination therapy and the implications of Pfkelch13 and Pfcoronin molecular markers in treatment failure in Senegal

In 2006, Senegal adopted artemisinin-based combination therapy (ACT) as first-line treatment in the management of uncomplicated malaria. This study aimed to update the status of antimalarial efficacy more than ten years after their first introduction. This was a randomized, three-arm, open-label study to evaluate the efficacy and safety of artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ) and dihydroartemisinin-piperaquine (DP) in Senegal. Malaria suspected patients were screened, enrolled, treated, and followed for 28 days for AL and ASAQ arms or 42 days for DP arm. Clinical and parasitological responses were assessed following antimalarial treatment. Genotyping (msp1, msp2 and 24 SNP-based barcode) were done to differentiate recrudescence from re-infection; in case of PCR-confirmed treatment failure, Pfk13 propeller and Pfcoronin genes were sequenced. Data was entered and analyzed using the WHO Excel-based application. A total of 496 patients were enrolled. In Diourbel, PCR non-corrected/corrected adequate clinical and parasitological responses (ACPR) was 100.0% in both the AL and ASAQ arms. In Kedougou, PCR corrected ACPR values were 98.8%, 100% and 97.6% in AL, ASAQ and DP arms respectively. No Pfk13 or Pfcoronin mutations associated with artemisinin resistance were found. This study showed that AL, ASAQ and DP remain efficacious and well-tolerated in the treatment of uncomplicated P. falciparum malaria in Senegal.

Evidence for treating malaria with artemisinin-based combination therapy in the first trimester of pregnancy

Evidence for treating malaria with artemisinin-based combination therapy in the first trimester of pregnancy

First trimester use of artemisinin-based combination therapy and the risk of low birth weight and small for gestational age

BackgroundWhile there is increasing evidence on the safety of artemisinin-based combination therapy (ACT) for the case management of malaria in early pregnancy, little is known about the association between exposure to ACT during the first trimester and the effect on fetal growth.MethodsData were analysed from prospective studies of pregnant women enrolled in Mozambique, Burkina Faso and Kenya designed to determine the association between anti-malarial drug exposure in the first trimester and pregnancy outcomes, including low birth weight (LBW) and small for gestational age (SGA). Exposure to anti-malarial drugs was ascertained retrospectively by record linkage using a combination of data collected from antenatal and adult outpatient clinic registries, prescription records and self-reported medication usage by the women. Site-level data synthesis (fixed effects and random effects) was conducted as well as individual-level analysis (fixed effects by site).ResultsOverall, 1915 newborns were included with 92 and 26 exposed to ACT (artemether–lumefantrine) and quinine, respectively. In Burkina Faso, Mozambique and Kenya at recruitment, the mean age (standard deviation) was 27.1 (6.6), 24.2 (6.2) and 25.7 (6.5) years, and the mean gestational age was 24.0 (6.2), 21.2 (5.7) and 17.9 (10.2) weeks, respectively. The LBW prevalence among newborns born to women exposed to ACT and quinine (QNN) during the first trimester was 10/92 (10.9%) and 7/26 (26.9%), respectively, compared to 9.5% (171/1797) among women unexposed to any anti-malarials during pregnancy. Compared to those unexposed to anti-malarials, ACT and QNN exposed women had the pooled LBW prevalence ratio (PR) of 1.13 (95% confidence interval (CI) 0.62–2.05, p-value 0.700) and 2.03 (95% CI 1.09–3.78, p-value 0.027), respectively. Compared to those unexposed to anti-malarials ACT and QNN-exposed women had the pooled SGA PR of 0.85 (95% CI 0.50–1.44, p-value 0.543) and 1.41 (95% CI 0.71–2.77, p-value 0.322), respectively. Whereas compared to ACT-exposed, the QNN-exposed had a PR of 2.14 (95% CI 0.78–5.89, p-value 0.142) for LBW and 8.60 (95% CI 1.29–57.6, p-value 0.027) for SGA. The level of between sites heterogeneity was moderate to high.ConclusionACT exposure during the first trimester was not associated with an increased occurrence of LBW or SGA. However, the data suggest a higher prevalence of LBW and SGA for children born to QNN-exposed pregnancies. The findings support the use of ACT (artemether–lumefantrine) for the treatment of uncomplicated malaria during the first trimester of pregnancy.

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

IntroductionArtemisinin-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.MethodsA 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.ResultsSix 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.ConclusionACTs 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.Electronic supplementary materialThe online version of this article (10.1007/s40268-018-0259-3) contains supplementary material, which is available to authorized users.

Efficacy and safety of artemisinin-based combination therapy, and molecular markers for artemisinin and piperaquine resistance in Mainland Tanzania

BackgroundArtemisinin-based combination therapy (ACT) is the first-line anti-malarial treatment of uncomplicated malaria in most malaria endemic countries, including Tanzania. Unfortunately, there have been reports of artemisinin resistance and ACT failure from South East Asia highlighting the need to monitor therapeutic efficacy of ACT in these countries as recommended by World Health Organization.MethodsOpen-label single arm studies in mainland Tanzania were conducted in nine sentinel sites in 2011, 2012 and 2015 to assess the efficacy and safety of artemether/lumefantrine (AL) and artesunate/amodiaquine (ASAQ) using 28 days follow-up and dihydroartemisinin/piperaquine (DHAPQ) using 42 days follow-up. Mutations in the propeller domain of the Plasmodium falciparum kelch 13 (k13) gene and amplification of the P. falciparum plasmepsin 2 (pm2) gene, associated with artemisinin and piperaquine (PQ) resistance, were also investigated.ResultsOf the 428 patients enrolled, 328 patients provided study endpoint. For AL, the PCR corrected per-protocol analysis showed adequate clinical and parasitological response (ACPR) of 90.3% (n = 28; 95% CI 74.2–98.0) in Kyela 2012, 95.7% (n = 22; 95% CI 78.1–99.0) in Chamwino, 100% in Muheza (n = 29; 95% CI 88.1–100), 100% in Nagaga (n = 39; 95% CI 91.0–100) and Kyela 2015 (n = 60; 95% CI 94.0–100). For ASAQ, PCR corrected ACPR of 98% (n = 49; 95% CI 89.4–99.9) and 100% (n = 25; 95% CI 86.3–100) were observed in 2011 in Ujiji and Kibaha, respectively. For DHAPQ, the ACPR was 100% (n = 71; 95% CI 94.9–100). Of the 235 samples with genetic interpretable results, only 7 (3%) had non-synonymous k13 mutations. None of these are candidate or validated markers of artemisinin resistance and all patients carrying these alleles cleared the parasites on day 3. Of the DHAPQ group, 10% (3/29) of the samples with interpretable results had pm2 multiple copies and none of them was associated with treatment failure.ConclusionAll the tested ACT in mainland Tanzania were highly efficacious and none of validated k13 mutants associated with artemisinin resistance was observed. However, three isolates with multiple copy numbers of pm2 gene associated with PQ resistance among the limited samples tested successfully calls for further investigation.Trial registration Number ACTRN12615000159550. Registered 18th February 2015, https://www.anzctr.org.au/trial/MyTrial.aspx

Efficacy and safety of artemisinin-based combination therapy for uncomplicated Plasmodium falciparum malaria in Sudan: a systematic review and meta-analysis

BackgroundMalaria is a major public health problem in endemic countries including Sudan, where about 75% of populations are at risk. Due to widespread of chloroquine-resistant strains of Plasmodium falciparum, artemisinin-based combination therapy (ACT) is currently treatment of choice for malaria in the vast majority of malaria-endemic countries. This systematic review and meta-analysis is performed to obtain an overall stronger evidence of the outcomes of ACT in the treatment of uncomplicated falciparum malaria from the existing literature in Sudan.MethodsThe preferred reporting items for systematic review and meta-analysis statement were used to select studies to be included in this review. A computerized systematic strategy was adopted to search articles from PubMed, Google Scholar and Science Direct databases. Unpublished materials were also included. Open Meta-Analyst software was used to perform the meta-analysis. Random effects model was used to combine the included studies and the heterogeneity of studies was assessed using Cochrane Q and I2 (χ2 = 73.05, df (19), P < 0.001 and I2 = 73.99).ResultsTwenty studies fulfilled the inclusion criteria (ACT in the treatment of uncomplicated falciparum malaria) and were included in the final analysis with a total number of 4070 participants. Malaria treatment outcome was assessed using World Health Organization guidelines. Adequate clinical and parasitological response was used to assess treatment success at the 28th day. Treatment success of all combined studies was 98% [(95% CI 97.2–98.8%), P < 0.001]. Treatment success was higher in malaria patients treated with artemether + lumefantrine (AL) than patients treated with artesunate + sulfadoxine–pyrimethamine (AS + SP) (98.9% (95% CI 98.4–99.4%) vs 97.1% (95% CI 95.5–98.6%), P < 0.001). Eleven studies reported adverse drug reactions (ADRs) to ACT (184 participants out of 3957 (4.65%). The ADRs were mild and resolved spontaneously. There was no severe ADRs or deaths.ConclusionBased on this review, the overall malaria treatment success was high (98%). AL regimen showed higher efficacy compared to AS + SP. The overall regimens were associated with mild low rates ADRs.

Efficacy and safety of artemisinin-based combination therapy and chloroquine with concomitant primaquine to treat Plasmodium vivax malaria in Brazil: an open label randomized clinical trial

BackgroundThere is general international agreement that the importance of vivax malaria has been neglected, and there is a need for new treatment approaches in an effort to progress towards control and elimination in Latin America. This open label randomized clinical trial evaluated the efficacy and safety of three treatment regimens using either one of two fixed dose artemisinin-based combinations or chloroquine in combination with a short course of primaquine (7–9 days: total dose 3–4.2 mg/kg) in Brazil. The primary objective was establishing whether cure rates above 90% could be achieved in each arm.ResultsA total of 264 patients were followed up to day 63. The cure rate of all three treatment arms was greater than 90% at 28 and 42 days. Cure rates were below 90% in all three treatment groups at day 63, although the 95% confidence interval included 90% for all three treatments. Most of the adverse events were mild in all treatment arms. Only one of the three serious adverse events was related to the treatment and significant drops in haemoglobin were rare.ConclusionThis study demonstrated the efficacy and safety of all three regimens that were tested with 42-day cure rates that meet World Health Organization criteria. The efficacy and safety of artemisinin-based combination therapy regimens in this population offers the opportunity to treat all species of malaria with the same regimen, simplifying protocols for malaria control programmes and potentially contributing to elimination of both vivax and falciparum malaria.Trial registration RBR-79s56s

Exposure to artemether-lumefantrine (Coartem) in first trimester pregnancy in an observational study in Zambia.

BackgroundIn general, safety data following exposure to drugs in the first trimester of pregnancy are scarce. More specifically, data on the safety of artemisinin-based combination therapy (ACT) in pregnancy still remain limited. Therefore, pregnant women from Choma, Zambia, who were exposed to artemether-lumefantrine (AL) for the treatment of uncomplicated malaria were followed up and evaluated in a prospective cohort study. This report assessed the longitudinal safety outcomes of the pregnant women inadvertently exposed during the first trimester.MethodsParticipants were classified based on the drug used to treat their most recent malaria episode: artemether-lumefantrine (AL) versus sulphadoxine-pyrimethamine (SP) and/or quinine. All enrolled women were followed up until six weeks post-delivery and the live births for 12 months.ResultsThere were 294 first trimester exposures in the observational cohort (pregnant women: AL = 150, AL and SP = 9 and SP and/or quinine = 135). Similar rates of perinatal mortality (stillbirths and neonatal deaths) were observed for each treatment arm (AL 4.4%, SP and/or quinine 3.9%). At delivery (newborns: AL = 135, AL and SP = 7 and SP and/or quinine = 129), the gestational age (measured using the Dubowitz total scores), length and head circumference of the newborns were similar between the two arms. Low birth weights were reported in 10.2% (95% CI 6.0, 16.6) and 6.7% (95% CI 3.4, 12.6) of newborns in the AL and SP and/or quinine arms, respectively. Overall development (including neurodevelopmental parameters) was similar between the two arms, both at 14 weeks and 12 months of age.ConclusionExposure to AL and SP in the first trimester was not associated with particular safety risks such as perinatal mortality, preterm deliveries or low birth weights. Such outcomes as well as infant neurodevelopmental parameters up to 12 months were similar between the two arms. These findings add to the body of data suggesting that randomized clinical trials could now be the way forward to assess safety and efficacy of ACT in the first trimester of pregnancy.

Probabilistic Record Linkage for Monitoring the Safety of Artemisinin-Based Combination Therapy in the First Trimester of Pregnancy in Senegal

There are insufficient data on the safety in early pregnancy of the artemisinins, a new class of antimalarials. Assessment of drug teratogenicity requires large sample sizes for an adequate risk-benefit assessment. There is currently limited pharmacovigilance infrastructure in malaria-endemic countries. Monitoring drug safety in early pregnancy is especially challenging, as it requires early pregnancy detection to assess any potential increased risk of miscarriage, prospective follow-up to reduce recall and survival biases, and accurate data on gestational age assessment. Record linkage approaches for pregnancy pharmacovigilance using routinely generated health records could be a pragmatic and cost-effective approach for pharmacovigilance in early pregnancy, but has not been evaluated in resource-poor settings. Our objective was to assess the feasibility of record linkage using routinely collected healthcare data as a pragmatic means of monitoring the safety in early pregnancy of artemisinin-based combination therapies (ACTs) in Senegal. Data (2004-2008) from paper-based registers from outpatient clinics, antenatal care services (ANC) and the delivery unit from the St Joseph dispensary in Mlomp, south-western Senegal, were entered into databases. Record linkage based on a probabilistic matching approach was used to identify pregnancies exposed to ACTs in the first trimester of pregnancy. Two record linkage software packages (Link-Plus and FRIL) were compared and output data were reviewed independently by two investigators. Information on 685 pregnancies was extracted, 536 of which were from the geographic catchment area and eligible for record linkage; 94.6% of them resulted in live births, 2.6% in stillbirths and 2.8% in miscarriages. Major congenital malformations were identified in 1.6% of births. Seventy-three and 75 true matches between pregnancy outcome and the outpatient treatment registers were identified by two different record linkage software packages, respectively. Record linkage identified seven exposures to ACTs in the first trimester, all of which resulted in normal live-births. Probabilistic record linkage is a potentially cost-effective method to assess the safety of antimalarials in early pregnancy in resource-constrained settings to assess increased risk of overall birth defects, and stillbirths in settings with good existing health records and well defined target populations.

Plasmodium falciparum Malaria in Infants Under 5 Kg: Retrospective Surveillance of Hospital Records in Five Sub-Saharan African Countries

To investigate the disease burden, clinical features, treatment and outcomes of Plasmodium falciparum malaria in neonates and infants weighing <5 kg in five sub-Saharan African countries. Pediatric hospital records were retrospectively reviewed for relevant cases. Details of clinical features, treatment and clinical outcomes were collected, and a descriptive analysis of data was carried out. The annual number of malaria cases ranged from 12 to 120 cases across hospitals and calendar years. The most frequent reason for seeking care was fever. Parasite density was low. Quinine was the most common treatment, followed by artemisinin-based combination therapy. The majority of patients recovered from their illness following treatment. Plasmodium falciparum malaria exists in this subpopulation. Further epidemiological data are needed to estimate malaria morbidity and mortality in young infants. Moreover, clinical evidence on the efficacy and safety of artemisinin-based combination therapies in this subpopulation is warranted.

Exploring meaning of participation in a clinical trial in a developing country setting: implications for recruitment

Objectives This study aimed to explore the experiences of people participating in a clinical trial in Tanzania. We sought to understand the meaning attached to participation and how experiences of being in the trial related to participants’ original motivations for consenting, in order to explore appropriate strategies for recruitment in a developing country setting. Methods We designed a qualitative study alongside a clinical observational trial of the efficacy and safety of artemisinin-based combination therapy (ACT) for malaria in patients concomitantly receiving antiretroviral therapy (ART) for HIV in Muheza, Tanzania. Focus-group discussions have been held with HIV-positive and HIVnegative people who have participated in the trial, and with HIV-positive people who were screened but who did not participate. This data has been triangulated with in-depth interviews with staff conducting the trial and delivering HIV care at the hospital where the trial was conducted. Data is being analysed using an iterative, line-by-line approach based on the principles of grounded theory, to identify units of meaning and develop themes and constructs from the data. Results Analysis to date of eight FGDs and IDIs indicates a disconnect between the information given to trial participants in the recruitment and consent process and their understanding of the trial and its aims, with a few participants stating they did not realise they were part of a research study. This reflects, and may be attributable to trial participants’ frequent conflation of the clinical encounter - testing for malaria - with the research encounter - the recruitment process - and an inability to distinguish between these as separate events. When describing recruitment, many participants framed their narrative around clinical events such as the malaria test and seeking treatment, the latter being considered the most important reason for joining the study. The clinical context in which participants were screened and recruited appeared to influence their ability to interpret information about the trial and expectations for what may happen to them, raising questions about the nature of ‘informed consent’ in the recruitment process. Participants reported overwhelmingly positive experiences of participating in the trial, largely based around their access to numerous tests and free treatment, as well as reimbursement for transport and telephone costs. Being part of the trial was frequently conceptualised as receiving a ‘service’, valued chiefly for enabling participants to be observed and to know their health status. The perceived value of this ‘service’ was reflected in many participants’ reports of encouraging friends and family to attend for malaria testing, in order to access the service associated with the trial. Although this indicates again some confusion between clinical and research activities, it appeared that the ‘enactment’ of the trial – giving and receiving the service – offered the social space in which participants were likely to raise any concerns about aspects of the trial. Such concerns included questioning the ‘true’ aim of the study, and fears over blood taking. This suggests that it is within a relationship of interaction with trial staff and activities that comprehension about the meaning and value of participation can begin to emerge, thus highlighting the

A randomized trial on effectiveness of artemether-lumefantrine versus artesunate plus amodiaquine for unsupervised treatment of uncomplicated Plasmodium falciparum malaria in Ghanaian children

BackgroundNumerous trials have demonstrated high efficacy and safety of artemisinin-based combination therapy (ACT) under supervised treatment. In contrast, effectiveness studies comparing different types of ACT applied unsupervised are scarce. The aim of this study was to compare effectiveness, tolerability and acceptance of artesunate plus amodiaquine (ASAQ) against that of artemether-lumefantrine (AL) in Ghanaian children with uncomplicated Plasmodium falciparum malaria.MethodsA randomized open-label trial was conducted at two district hospitals in the Ashanti region, Ghana, an area of intense malaria transmission. A total of 246 children under five years of age were randomly assigned to either ASAQ (Arsucam®) or AL (Coartem®). Study participants received their first weight-adjusted dose under supervision. After the parent/guardian was advised of times and mode of administration the respective three-day treatment course was completed unobserved at home. Follow-up visits were performed on days 3, 7, 14 and 28 to evaluate clinical and parasitological outcomes, adverse events, and haematological recovery. Length polymorphisms of variable regions of msp1 and msp2 were determined to differentiate recrudescences from reinfections. Acceptance levels of both treatment regimens were assessed by means of standardized interviews.ResultsAdequate clinical and parasitological responses after AL and ASAQ treatment were similar (88.3% and 91.7%, respectively). Interestingly, more late clinical failures until day 28 occurred in AL-treated children than in those who received ASAQ (17.5% and 7.3%, respectively; Hazard Ratio 2.41, 95% CI 1.00–5.79, p < 0.05).Haematological recovery and drug tolerability were not found to be significantly different in both study arms. The acceptance of treatment with ASAQ was higher than that with AL (rank-scores 10.6 and 10.3, respectively; p < 0.05).ConclusionUnobserved AL and ASAQ treatment showed high adequate clinical and parasitological responses, though AL was inferior in preventing late clinical failures.

Artemisinin-based combination therapies (ACTs): Best hope for malaria treatment but inaccessible to the needy!

Artemisinin-based combination therapies (ACTs) are the best anti-malarial drugs available now. Artemisinin enhances efficacy and has the potential of lowering the rate at which resistance emerges and spreads. Under low transmission intensity, ACTs have an additional public health benefit of reducing the overall malaria transmission and studies are urgently needed to investigate modalities of attaining similar benefits under high transmission. Despite being recommended by WHO since 2001, overall deployment of ACT has been slow. Limiting factors are high cost, limited knowledge and public awareness on the concept of combination therapy (CT) and ACT in particular, limited knowledge on safety of ACTs in pregnancy, operational issue such as inappropriate drug use, lack of suitable drug formulations, lack of post-marketing surveillance (PMS) systems, and the imbalance between demand and supply. Through concerted efforts of multilateral organizations, the local scientific community with involvement of policy-makers progress has been on several fonts leading to improved ACT uptake rates in the last 2 years. Of 43 countries that had adopted ACT by February 2005, 18 (42%) adopted the policy in 2004. Preference to co-formulated Coartem has led to a surge in its demand with consequent shortage. Alternative ways for increased production of ACTs are urgently needed otherwise most policies will remain adopted on paper. Despite limitations, opportunities are opening up for effective malaria control. Insecticides, insecticide-treated nets (ITNs) and ACTs are proven efficacious controls available that should be accessed by many. Substantial funding is now available for biomedical malaria research and for policy implementation. While the Global Fund is the financial engine behind the scaling up of ACT uptake, delays in cash flow after grant approval has led to many countries adopting ACT in 2004 but only few (nine) implementing it. Clear policies on granted funds and minimal politics within funding agencies might improve the situation. Increased interest in drug development together with the public and private sector partnership have led to new anti-malarials, some less expensive and therefore affordable by poor malaria endemic countries. Dihydroartemisinin-piperaquine (Artekin) has a cost advantage over other ACTs (US$ 1 for an adult treatment) making it a potential best candidate for deployment in Africa. Part of available funds should be invested into capacity building and strengthening (personnel, resources and infrastructure) of institutions in malaria endemic countries. This will create enabling environment and a critical mass of scientists and public health experts to spearhead ACT policy implementation. Active involvement of scientists from malaria endemic countries in recent International Scientific Forums like the Malaria in Pregnancy Working Group and the Consortium on ACT Implementation is the best way forward to emulate.