Safety and efficacy of co-trimoxazole for treatment and prevention of Plasmodium falciparum malaria: a systematic review.

INTRODUCTION: Cotrimoxazole (CTX) has been used for half a century. It is inexpensive hence the reason for its almost universal availability and wide clinical spectrum of use. In the last decade, CTX was used for prophylaxis of opportunistic infections in HIV infected people. It also had an impact on the malaria risk in this specific group. OBJECTIVE: We performed a systematic review to explore the efficacy and safety of CTX used for P.falciparum malaria treatment and prophylaxis. RESULT: CTX is safe and efficacious against malaria. Up to 75% of the safety concerns relate to skin reactions and this increases in HIV/AIDs patients. In different study areas, in HIV negative individuals, CTX used as malaria treatment cleared 56%-97% of the malaria infections, reduced fever and improved anaemia. CTX prophylaxis reduces the incidence of clinical malaria in HIV-1 infected individuals from 46%-97%. In HIV negative non pregnant participants, CTX prophylaxis had 39.5%-99.5% protective efficacy against clinical malaria. The lowest figures were observed in zones of high sulfadoxine-pyrimethamine resistance. There were no data reported on CTX prophylaxis in HIV negative pregnant women. CONCLUSION: CTX is safe and still efficacious for the treatment of P.falciparum malaria in non-pregnant adults and children irrespective of HIV status and antifolate resistance profiles. There is need to explore its effect in pregnant women, irrespective of HIV status. CTX prophylaxis in HIV infected individuals protects against malaria and CTX may have a role for malaria prophylaxis in specific HIV negative target groups

European and Developing Countries Clinical Trials Partnership (EDCTP): the path towards a true partnership

European and Developing Countries Clinical Trials Partnership (EDCTP) was founded in 2003 by the European Parliament and Council. It is a partnership of 14 European Union (EU) member states, Norway, Switzerland, and Developing Countries, formed to fund acceleration of new clinical trial interventions to fight the human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS), malaria and tuberculosis (TB) in the sub-Saharan African region. EDCTP seeks to be synergistic with other funding bodies supporting research on these diseases. EDCTP promotes collaborative research supported by multiple funding agencies and harnesses networking expertise across different African and European countries. EDCTP is different from other similar initiatives. The organisation of EDCTP blends important aspects of partnership that includes ownership, sustainability and responds to demand-driven research. The Developing Countries Coordinating Committee (DCCC); a team of independent scientists and representatives of regional health bodies from sub-Saharan Africa provides advice to the partnership. Thus EDCTP reflects a true partnership and the active involvement and contribution of these African scientists ensures joint ownership of the EDCTP programme with European counterparts. The following have been the major achievements of the EDCTP initiative since its formation in 2003; i) increase in the number of participating African countries from two to 26 in 2008 ii) the cumulative amount of funds spent on EDCTP projects has reached 150 m euros, iii) the cumulative number of clinical trials approved has reached 40 and iv) there has been a significant increase number and diversity in capacity building activities. While we recognise that EDCTP faced enormous challenges in its first few years of existence, the strong involvement of African scientists and its new initiatives such as unconditional funding to regional networks of excellence in sub-Saharan Africa is envisaged to lead to a sustainable programme. Current data shows that the number of projects supported by EDCTP is increasing. DCCC proposes that this success story of true partnership should be used as model by partners involved in the fight against other infectious diseases of public health importance in the region

First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies.

BACKGROUND: Animal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment. METHODS AND FINDINGS: Electronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model. There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08-1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36-1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6-12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54-2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26-2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52-2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%-3.5%]) and quinine exposures (1.2% [95% CI 0.6%-2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns. CONCLUSIONS: Compared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens. REVIEW REGISTRATION: PROSPERO CRD42015032371

Safety of daily co-trimoxazole in pregnancy in an area of changing malaria epidemiology: a phase 3b randomized controlled clinical trial.

INTRODUCTION: Antibiotic therapy during pregnancy may be beneficial and impacts positively on the reduction of adverse pregnancy outcomes. No studies have been done so far on the effects of daily Co-trimoxazole (CTX) prophylaxis on birth outcomes. A phase 3b randomized trial was conducted to establish that daily CTX in pregnancy is not inferior to SP intermittent preventive treatment (IPT) in reducing placental malaria; preventing peripheral parasitaemia; preventing perinatal mortality and also improving birth weight. To establish its safety on the offspring by measuring the gestational age and birth weight at delivery, and compare the safety and efficacy profile of CTX to that of SP. METHODS: Pregnant women (HIV infected and uninfected) attending antenatal clinic were randomized to receive either daily CTX or sulfadoxine-pyrimethamine as per routine IPT. Safety was assessed using standard and pregnancy specific measurements. Women were followed up monthly until delivery and then with their offspring up to six weeks after delivery. RESULTS: Data from 346 pregnant women (CTX = 190; SP = 156) and 311 newborns (CTX = 166 and SP = 145) showed that preterm deliveries (CTX 3.6%; SP 3.0%); still births (CTX 3.0%; SP 2.1%), neonatal deaths (CTX 0%; SP 1.4%), and spontaneous abortions (CTX 0.6%; SP 0%) were similar between study arms. The low birth weight rates were 9% for CTX and 13% for SP. There were no birth defects reported. Both drug exposure groups had full term deliveries with similar birth weights (mean of 3.1 Kg). The incidence and severity of AEs in the two groups were comparable. CONCLUSION: Exposure to daily CTX in pregnancy may not be associated with particular safety risks in terms of birth outcomes such as preterm deliveries, still births, neonatal deaths and spontaneous abortions compared to SP. However, more data are required on CTX use in pregnant women both among HIV infected and un-infected individuals. TRIAL REGISTRATION: Clinicaltrials.gov NCT00711906

Safety profile of Coartem®: the evidence base

This article reviews the comprehensive data on the safety and tolerability from over 6,300 patients who have taken artemether/lumefantrine (Coartem®) as part of Novartis-sponsored or independently-sponsored clinical trials. The majority of the reported adverse events seen in these studies are mild or moderate in severity and tend to affect the gastrointestinal or nervous systems. These adverse events, which are common in both adults and children, are also typical of symptoms of malaria or concomitant infections present in these patients. The wealth of safety data on artemether/lumefantrine has not identified any neurological, cardiac or haematological safety concerns. In addition, repeated administration is not associated with an increased risk of adverse drug reactions including neurological adverse events. This finding is especially relevant for children from regions with high malaria transmission rates who often receive many courses of anti-malarial medications during their lifetime. Data are also available to show that there were no clinically relevant differences in pregnancy outcomes in women exposed to artemether/lumefantrine compared with sulphadoxine-pyrimethamine during pregnancy. The six-dose regimen of artemether/lumefantrine is therefore well tolerated in a wide range of patient populations. In addition, post-marketing experience, based on the delivery of 250 million treatments as of July 2009, has not identified any new safety concerns for artemether/lumefantrine apart from hypersensitivity and allergies, known class effects of artemisinin derivatives

Efficacy, Safety and Tolerability of Pyronaridine-artesunate in Asymptomatic Malaria-infected Individuals: a Randomized Controlled Trial

BACKGROUND: Pyronaridine-artesunate (PA) is a registered artemisinin-based combination therapy, potentially useful for mass drug administration campaigns. However, further data are needed to evaluate its efficacy, safety and tolerability as full or incomplete treatment in asymptomatic Plasmodium falciparum-infected individuals. METHODS: This phase II, multi-center, open label, randomized clinical trial was conducted in The Gambia and Zambia. Participants with microscopically confirmed asymptomatic P. falciparum infection were randomly assigned (1:1:1) to receive a 3-day, 2-day, or 1-day treatment regimen of PA (180:60 mg), dosed according to bodyweight. The primary efficacy outcome was polymerase chain reaction (PCR)-adjusted adequate parasitological response (APR) at day 28 in the per-protocol population. RESULTS: A total of 303 participants were randomized. Day 28 PCR-adjusted APR was 100% for both the 3-day (98/98) and 2-day regimens (96/96), and 96.8% (89/94) for the 1-day regimen. Efficacy was maintained at 100% until day 63 for the 3-day and 2-day regimens but declined to 94.4% (84/89) with the 1-day regimen. Adverse event frequency was similar between the 3-day (51.5% [52/101]), 2-day (52.5% [52/99]), and 1-day (54.4% [56/103]) regimens; the majority of adverse events were of grade 1 or 2 severity (85% [136/160]). Asymptomatic, transient increases (>3 times the upper limit of normal) in alanine aminotransferase/aspartate aminotransferase were observed for 6/301 (2.0%) participants. CONCLUSIONS: PA had high efficacy and good tolerability in asymptomatic P. falciparum-infected individuals, with similar efficacy for the full 3-day and incomplete 2-day regimens. Although good adherence to the 3-day regimen should be encouraged, these results support the further investigation of PA for mass drug administration campaigns. CLINICAL TRIALS REGISTRATION: NCT03814616

Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: A systematic review and individual patient data meta-analysis

Background Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. Methods For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. Findings We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49–1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47–1·17), stillbirth (aHR=0·71, 0·32–1·57), and major congenital anomalies (aHR=0·60, 0·13–2·87). The risk of adverse pregnancy outcomes was lower with artemether–lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36–0·92). Interpretation We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether–lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether–lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether–lumefantrine is unavailable, other ACTs (except artesunate–sulfadoxine–pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted