Saadou Issifou

Fosmidomycin for malaria

Safe and effective antimalarial drugs with new methods of action are urgently needed. Fosmidomycin inhibits the synthesis of isoprenoid by Plasmodium falciparum, and suppresses the growth of multidrug-resistant strains in vitro. Our aim was to assess the efficacy and tolerability of fosmidomycin in adults with malaria in Gabon. We administered the drug for 5, 4, or 3 days (1.2 g every 8 h), in nine, eight, and ten evaluable patients, respectively. All treatment regimens were well tolerated. Cure rates by day 14 were 89% (eight of nine), 88% (seven of eight), and 60% (six of ten), for treatment durations of 5, 4, and 3 days, respectively. These data suggest that fosmidomycin is a safe and effective treatment for uncomplicated malaria if given for 4 days or more.

Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials

BACKGROUND Intermittent preventive treatment (IPT) is a promising strategy for malaria control in infants. We undertook a pooled analysis of the safety and efficacy of IPT in infants (IPTi) with sulfadoxine-pyrimethamine in Africa. METHODS We pooled data from six double-blind, randomised, placebo-controlled trials (undertaken one each in Tanzania, Mozambique, and Gabon, and three in Ghana) that assessed the efficacy of IPTi with sulfadoxine-pyrimethamine. In all trials, IPTi or placebo was given to infants at the time of routine vaccinations delivered by WHOs Expanded Program on Immunization. Data from the trials for incidence of clinical malaria, risk of anaemia (packed-cell volume <25% or haemoglobin <80 g/L), and incidence of hospital admissions and adverse events in infants up to 12 months of age were reanalysed by use of standard outcome definitions and time periods. Analysis was by modified intention to treat, including all infants who received at least one dose of IPTi or placebo. FINDINGS The six trials provided data for 7930 infants (IPTi, n=3958; placebo, n=3972). IPTi had a protective efficacy of 30.3% (95% CI 19.8-39.4, p<0.0001) against clinical malaria, 21.3% (8.2-32.5, p=0.002) against the risk of anaemia, 38.1% (12.5-56.2, p=0.007) against hospital admissions associated with malaria parasitaemia, and 22.9% (10.0-34.0, p=0.001) against all-cause hospital admissions. There were 56 deaths in the IPTi group compared with 53 in the placebo group (rate ratio 1.05, 95% CI 0.72-1.54, p=0.79). One death, judged as possibly related to IPTi because it occurred 19 days after a treatment dose, was subsequently attributed to probable sepsis. Four of 676 non-fatal hospital admissions in the IPTi group were deemed related to study treatment compared with five of 860 in the placebo group. None of three serious dermatological adverse events in the IPTi group were judged related to study treatment compared with one of 13 in the placebo group. INTERPRETATION IPTi with sulfadoxine-pyrimethamine was safe and efficacious across a range of malaria transmission settings, suggesting that this intervention is a useful contribution to malaria control. FUNDING Bill & Melinda Gates Foundation.

Fosmidomycin-Clindamycin for the Treatment of Plasmodium falciparum Malaria

It has been demonstrated that fosmidomycin has good tolerability and rapid onset of action, but late recrudescences preclude its use alone; in vitro, clindamycin has been shown to act synergistically with fosmidomycin against Plasmodium falciparum. We conducted a study in pediatric outpatients with P. falciparum malaria in Gabon to evaluate the efficacy and safety of an oral combination of fosmidomycin-clindamycin of 30 mg/kg and 10 mg/kg of body weight, respectively, every 12 h. Patients 7-14 years old were recruited in cohorts of 10. The first 10 patients were treated for 5 days. The duration of treatment was then incrementally shortened in intervals of 1 day if >85% of the patients in a cohort were cured by day 14. All dosing regimens were well tolerated, and no serious adverse events occurred. Asexual parasites and fever rapidly cleared in all patients. Cure ratios of 100% on day 14 were achieved with treatment durations of 5 (10/10 patients), 4 (10/10 patients), 3 (10/10 patients), and 2 days (10/10 patients); 1 day of treatment led to a cure ratio of 50% (5/10 patients). Fosmidomycin-clindamycin is safe and well tolerated, and short-course regimens achieved high efficacy in children with P. falciparum malaria. Fosmidomycin-clindamycin is a promising novel treatment option for malaria.

Placental Malaria Increases Malaria Risk in the First 30 Months of Life

BACKGROUND Plasmodium falciparum infection during pregnancy is associated with stillbirth, fetal growth restriction, and low birth weight. An additional consequence may be increased risk of malaria in early life, although the epidemiological evidence of this consequence is limited. METHODS A cohort of 527 children were observed actively every month for 30 months after delivery. Offspring of mothers with microscopically detectable placental P. falciparum infection at the time of delivery were defined as exposed. The outcome measure was malaria (parasitemia and fever). Analyses were performed using Cox proportional hazard models and were stratified by gravidity. RESULTS Overall, offspring of mothers with placental P. falciparum infection had a significantly higher risk of clinical malaria during the first 30 months of life (adjusted hazard ratio, 2.1; 95% confidence interval [CI], 1.2-3.7). The adjusted hazard ratio for offspring of multigravidae was 2.6 (95% CI, 1.3-5.3), and that for primigravidae was 1.5 (95% CI, 0.6-3.8). The offspring of placenta-infected primigravidae had no episodes of malaria during the first year of life. CONCLUSIONS Our findings show that active placental P. falciparum infection detected at delivery is associated with an approximately 2-fold greater risk of malaria during early life, compared with noninfection. The fact that persons born to infected multigravidae rather than primigravidae appear to be at greater risk emphasizes the importance of preventing malaria in mothers of all gravidities.

Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial

BACKGROUND The RTS,S/AS01(E) candidate malaria vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01(E) when integrated into the EPI. We report extended follow-up to 19 months, including efficacy results. METHODS We did a randomised, open-label, phase 2 trial of safety and efficacy of the RTS,S/AS01(E) candidate malaria vaccine given with EPI vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6-10 weeks of age at first vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus influenzae type b vaccine, and oral polio vaccine at study months 0, 1, and 2, and measles vaccine and yellow fever vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01(E) at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefined block list with a computer-generated randomisation code. Detection of serious adverse events and malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007. FINDINGS 511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01(E) 0, 1, 2 month group (34%, 95% CI 27-41), 47 in the 0, 1, 7 month group (28%, 21-35), and 49 (29%, 22-36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were significantly higher in the RTS,S/AS01(E) groups than in the control group. Vaccine efficacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site-adjusted according-to-protocol analysis) was 53% (95% CI 26-70; p=0·0012) against first malaria episodes and 59% (36-74; p=0·0001) against all malaria episodes. For the entire study period, (total vaccinated cohort) vaccine efficacy against all malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33-73; p=0·0002) than with the 0, 1, 7 month schedule (32% CI 16-45; p=0·0003). 1 year after dose three, vaccine efficacy against first malaria episodes was similar for both schedules (0, 1, 2 month group, 61·6% [95% CI 35·6-77·1], p<0·001; 0, 1, 7 month group, 63·8% [40·4-78·0], p<0·001, according-to-protocol cohort). INTERPRETATION Vaccine efficacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a first-generation malaria vaccine. The 0, 1, 2 month vaccine schedule has been selected for phase 3 candidate vaccine assessment. FUNDING Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals.

Fosmidomycin-Clindamycin for Plasmodium falciparum Infections in African Children

BACKGROUND Fosmidomycin is a new antimalarial drug with a novel mechanism of action. Studies in Africa that have evaluated fosmidomycin as monotherapeutic agent demonstrated its excellent tolerance, but 3-times-daily treatment regimens of >or=4 days were required to achieve radical cure, prompting further research to identify and validate a suitable combination partner to enhance its efficacy. METHODS We conducted a randomized, controlled, open-label study to evaluate the efficacy and safety of fosmidomycin combined with clindamycin (n=12; 30 and 5 mg/kg body weight every 12 h for 5 days, respectively), compared with fosmidomycin alone (n=12; 30 mg/kg body weight every 12 h for 5 days) and clindamycin alone (n=12; 5 mg/kg body weight every 12 h for 5 days) for the clearance of asymptomatic Plasmodium falciparum infections in schoolchildren in Gabon aged 7-14 years. RESULTS Asexual parasites were rapidly cleared in children treated with fosmidomycin-clindamycin (median time, 18 h) and fosmidomycin alone (25 h) but slowly in children treated with clindamycin alone (71 h; P=.004). However, only treatment with fosmidomycin-clindamycin or clindamycin alone led to the radical elimination of asexual parasites as measured by day 14 and 28 cure rates of 100%. Asexual parasites reappeared by day 28 in 7 children who received fosmidomycin (day 14 cure rate, 92% [11/12; day 28 cure rate, 42% [5/12]). All regimens were well tolerated, and no serious adverse events occurred. CONCLUSION The combination of fosmidomycin and clindamycin is well tolerated and superior to either agent on its own with respect to the rapid and radical clearance of P. falciparum infections in African children.

Fosmidomycin plus Clindamycin for Treatment of Pediatric Patients Aged 1 to 14 Years with Plasmodium falciparum Malaria

ABSTRACT Fosmidomycin plus clindamycin was shown to be efficacious in the treatment of uncomplicated Plasmodium falciparum malaria in a small cohort of pediatric patients aged 7 to 14 years, but more data, including data on younger children with less antiparasitic immunity, are needed to determine the potential value of this new antimalarial combination. We conducted a single-arm study to improve the precision of efficacy estimates for an oral 3-day fixed-ratio combination of fosmidomycin and clindamycin at 30 and 10 mg/kg of body weight, respectively, every 12 hours for the treatment of uncomplicated P. falciparum malaria in 51 pediatric outpatients aged 1 to 14 years. Fosmidomycin plus clindamycin was generally well tolerated, but relatively high rates of treatment-associated neutropenia (8/51 [16%]) and falls of hemoglobin concentrations of ≥2 g/dl (7/51 [14%]) are of concern. Asexual parasites and fever were cleared within median periods of 42 h and 38 h, respectively. All patients who could be evaluated were parasitologically and clinically cured by day 14 (49/49; 95% confidence interval [CI], 93 to 100%). The per-protocol, PCR-adjusted day 28 cure rate was 89% (42/47; 95% CI, 77 to 96%). Efficacy appeared to be significantly reduced in children aged 1 to 2 years, with a day 28 cure rate of only 62% for this small subgroup (5/8). The inadequate efficacy in children of <3 years highlights the need for continued systematic studies of the current dosing regimen, which should include randomized trial designs.

Fixed-Dose Pyronaridine-Artesunate Combination for Treatment of Uncomplicated Falciparum Malaria in Pediatric Patients in Gabon

BACKGROUND The development of novel artemisinin-combination therapies suitable for the treatment of pediatric patients suffering from malaria is a research priority. The aim of this study was to investigate a novel fixed-dose pyronaridine-artesunate combination for the treatment of uncomplicated falciparum malaria in Gabonese patients 2-14 years old. METHODS The study was designed as an open-label dose-escalation study recruiting 60 pediatric patients sequentially in 4 treatment cohorts: study drugs were administered once daily for 3 days, as tablet coformulations (pyronaridine:artesunate ratios of 6:2, 9:3, and 12:4 mg/kg) and as a granule coformulation (pyronaridine:artesunate ratio of 9:3 mg/kg). The primary end points were tolerability, safety, and pharmacokinetics of pyronaridine-artesunate treatment. Efficacy was treated as a secondary outcome measure. RESULTS The drugs had a good tolerability and safety profile, at all dose levels. Pharmacokinetic analysis revealed a dose-dependent increase in the maximum plasma/blood concentration and the area under the curve, as well as comparable relative bioavailability for the granule coformulation. Polymerase chain reaction-corrected cure rates at day 28 were 100% in per-protocol analysis, at all dose levels. CONCLUSIONS Pyronaridine-artesunate is a promising novel artemisinin-combination therapy for pediatric patients with uncomplicated Plasmodium falciparum malaria, and the development of both the tablet and the granule coformulations is warranted.

Intermittent Preventive Treatment against Malaria in Infants in Gabon-A Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND Intermittent preventive treatment aims to maximize the protective effects of malaria chemoprophylaxis while minimizing the deleterious effects. METHODS In Gabon, 1189 infants received either sulfadoxine-pyrimethamine (SP; 250 and 12.5 mg, respectively) or placebo at 3, 9, and 15 months of age. Children were actively followed-up until 18 months of age. RESULTS In the intention-to-treat population at 18 months of follow-up, 84 children (17%) in the SP group had > or =1 episode of anemia, versus 108 (21%) in the placebo group (protective efficacy, 22% [95% confidence interval {CI}, -1% to 40%]; P=.06). In the intervention group, there were 66 episodes during 485 person-years at risk, compared with 79 episodes during 497 years in the placebo group (protective efficacy, 17% [95% CI, -24% to 45%; P=.36). The effects were similar at 12 months of follow-up. The study drug was safe and well tolerated. CONCLUSIONS The intervention was efficacious, producing a reduction in risk for anemia but a smaller effect against malaria. It is a valuable additional tool to control malaria in a highly vulnerable age group. Remaining important questions are currently being addressed in further studies. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00167843.

A randomized trial assessing the safety and immunogenicity of AS01 and AS02 adjuvanted RTS,S malaria vaccine candidates in children in Gabon.

Background The malaria vaccine candidate antigen RTS,S includes parts of the pre-erythrocytic stage circumsporozoite protein fused to the Hepatitis B surface antigen. Two Adjuvant Systems are in development for this vaccine, an oil-in water emulsion – based formulation (AS02) and a formulation based on liposomes (AS01). Methods & Principal Findings In this Phase II, double-blind study (NCT00307021), 180 healthy Gabonese children aged 18 months to 4 years were randomized to receive either RTS,S/AS01E or RTS,S/AS02D, on a 0–1–2 month vaccination schedule. The children were followed-up daily for six days after each vaccination and monthly for 14 months. Blood samples were collected at 4 time-points. Both vaccines were well tolerated. Safety parameters were distributed similarly between the two groups. Both vaccines elicited a strong specific immune response after Doses 2 and 3 with a ratio of anti-CS GMT titers (AS02D/AS01E) of 0.88 (95% CI: 0.68–1.15) post-Dose 3. After Doses 2 and 3 of experimental vaccines, anti-CS and anti-HBs antibody GMTs were higher in children who had been previously vaccinated with at least one dose of hepatitis B vaccine compared to those not previously vaccinated. Conclusions RTS,S/AS01E proved similarly as well tolerated and immunogenic as RTS,S/AS02D, completing an essential step in the age de-escalation process within the RTS,S clinical development plan. Trial Registration ClinicalTrials.gov. NCT00307021