Pregnant women participating in a longitudinal immuno-epidemiologic survey in Lambaréné, Gabon, and presenting with Plasmodium falciparum parasitemia at monthly blood smear examinations were offered treatment with oral 7-day quinine monotherapy according to national health guidelines. A total of 50 pregnant women were offered 7-day oral quinine sulfate 10 mg/kg thrice daily. Clinical examinations and laboratory tests were performed on Days 28 and 56 to assess the effectiveness of this standard regimen. By Day 28, the effectiveness of the 7-day quinine regimen was 60% (95% confidence interval: 46-72%). We conclude that a 7-day course of quinine has a poor effectiveness and that alternative treatment regimens for malaria in pregnant women should be assessed.

Direct data entry, using handheld computers, may simplify and streamline data management, especially in remote settings. We compared the accuracy of data entry using the current standard practice (a paper-based case report form with double data entry) with that using a personal digital assistant (PDA) in a clinical study in rural Gabon. The rate of discrepant entries was 1.7%. Categorical data (presented in "pull down" menus on the PDA) were more commonly discrepant than were continuous "typed in" data (2.4% versus 1.2%; P = 0.001). Both systems functioned smoothly and no data were lost. The clinicians involved in this study preferred the handheld computers, and their use will be considered in future studies in an African clinical research network.

Severe and fatal malaria is associated with the increased presence of malaria hemozoin in peripheral phagocytes. Large studies of this relationship are hampered by the fact that identifying and counting phagocytes on thick blood smears is time consuming. Distinguishing which mononuclear cells are monocytes and which granulocytes are neutrophils requires time and careful training. In this study, we evaluated a simplified method in which only the proportions of hemozoin-containing mononuclear cells and granulocytes are counted. Thick blood films from 471 Gabonese children with malaria were evaluated. We found a linear relationship and a strong correlation between the proportions of hemozoin-containing monocytes versus mononuclear cells (r = 0.85) and neutrophils versus polymorphonuclear cells (r = 0.93), respectively. The two methods had similar predictive values, as estimated by receiver operating characteristics curves. This simplified method can be used to estimate the amount of extra-erythrocytic pigment in peripheral blood, and we suggest that it may be particularly suitable for very large studies.

Background. Several studies have shown an inverse association between helminth infections and atopy, but none have clearly established that the pathogens themselves, rather than other associated factors, cause the suppression of atopy. To show a direct link, prospective intervention studies are required.Methods. A randomized, controlled trial was performed to study whether repeated anthelminthic treatment results in increased allergic sensitivity to house dust mites (HDMs) in chronically infected children. The trial population consisted of 317 Gabonese schoolchildren with a high prevalence of intestinal helminths. Intervention consisted of treatment every 3 months with praziquantel and mebendazole and with placebo in the control group. Follow-up lasted 30 months: at 6-month intervals, skin-test sensitivity to mites, helminth infection status, and levels of total IgE were determined.Results. Treatment resulted in a significant increase in the rate of developing skin sensitivity to HDMs ( hazard ratio, 2.51; 95% confidence interval, 1.85-3.41), which was mediated, in part, by reductions in Ascaris and/or Trichuris infections. Levels of total IgE were reduced, but this did not mediate the effect of treatment on skin-test reactivity.Conclusions. Anthelminthic treatment of chronically infected children results in increased atopic reactivity, which indicates that helminths directly suppress allergic reactions.

BACKGROUND:Increasing resistance to sulfadoxine-pyrimethamine is leading to a decline in its effectiveness. We aimed to assess the safety profile of chlorproguanil-dapsone (CD), and to compare the safety and efficacy of this drug with that of sulfadoxine-pyrimethamine (SP) as treatment for uncomplicated falciparum malaria.METHODS:We undertook a double-blind, randomised trial in 1850 consecutively recruited children with uncomplicated falciparum malaria, pooling data from five African countries. Analyses were based on all randomised patients with available data.FINDINGS:CD was significantly more efficacious than SP (odds ratio 3.1 [95% CI 2.0-4.8]); 1313 patients (96%) given CD and 306 (89%) given SP achieved acceptable clinical and parasitological response by day 14. Adverse events were reported in 46% and 50% of patients randomised to CD and SP, respectively (treatment difference -4.4%, [95% CI -10.1 to 1.3]). Haemoglobin in the CD group was significantly lower than in the SP group at day 7, a difference of -4 g/L (95% CI -6 to -2). Mean day 14 haemoglobin (measured only for the small number of patients whose day 7 data caused concern) was 94 g/L (92-96) and 97 g/L (92-102) after CD and SP, respectively. Glucose-6-phosphate dehydrogenase deficient patients on CD had greater odds than those on SP of having a fall of 20 g/dL or more in haemoglobin when baseline temperature was high. Methaemoglobinaemia was seen in the CD group (n=320, mean 0.4% [95% CI 0.4-0.4]) before treatment, 4.2% (95% CI 3.8-4.6) (n=301) at day 3, and 0.6% (0.6-0.7) (n=300) at day 7).INTERPRETATION:CD had greater efficacy than SP in Africa and was well tolerated. Haematological adverse effects were more common with CD than with SP and were reversible. CD is a useful alternative where SP is failing due to resistance.

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.

ABSTRACT Artesunate is one of the most important antimalarial agents available, since it is effective against parasites that have developed resistance to conventional antimalarials in sub-Saharan Africa. Antimalarial combination chemotherapies with artesunate (4 mg/kg of body weight once daily for 3 days) as one partner have been proposed. However, the efficacy of a 3-day course of artesunate alone has never been evaluated in individuals in Africa (which has 90% of the worldwide malaria burden) living in regions of hyperendemicity, where a considerable degree of immunity might substantially enhance the efficacy of short courses of artesunate compared to those in regions where the levels of endemicity are low. This lack of information does not permit a systematic assessment of the value of artesunate-based combination chemotherapies in Africa. Therefore, we studied the efficacy and safety of a 3-day course of artesunate (4 mg/kg of body weight, orally, once daily) for the treatment of uncomplicated Plasmodium falciparum malaria in Gabonese patients aged 4 to 15 years (n = 50). Artesunate was well tolerated, and no severe adverse event was reported. Parasite elimination was rapid and was achieved in all patients within ≤72 h (geometric mean time to elimination, 34 h). The PCR-corrected cure rate by day 14 was 92% (46 of 50 patients), but it dropped to 72% (36 of 50 patients) by day 28. We conclude that a 3-day course of artesunate fails to achieve sufficiently high cure rates for uncomplicated falciparum malaria in Gabonese children.

The relationship between the efficacy of amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria and preexisting antibodies against merozoite surface protein (MSP)-1, a blood-stage P. falciparum antigen, was investigated. The immunoglobulin G antibody response to different MSP-1 recombinant proteins was evaluated in plasma samples from Gabonese children with uncomplicated malaria who were treated with amodiaquine. The prevalence of anti-MSP-1 antibodies was similar among patients with either parasitological and clinical cure after treatment (n=102) or treatment failure (n=51) by day 28 (83% in both groups). However, associations between antibody responses to K1 and MAD20 allelic families and therapeutic success were found (P< .001 and P= .034, respectively). A high proportion of plasma samples recognizing several antigens was found in the cured group. This association was significant even when data were stratified by age, particularly for the K1 family antigens (P= .029). These results suggest that humoral immune responses play a supportive role in the efficacy of amodiaquine treatment.

Malaria-related morbidity and mortality are greatest among young children in areas with high malaria transmission intensity. An open-label, randomized study was done to evaluate the efficacy and safety of the combination of atovaquone and proguanil formulated as pediatric-strength tablets (20 and 8 mg/kg of body weight, respectively, administered once daily for 3 days), compared with amodiaquine (10 mg/kg of body weight, once daily for 3 days), among children weighing > or =5 and <11 kg in Gabon. Two hundred patients aged 3-43 months were recruited. Use of atovaquone/proguanil resulted in a cure rate on day 28 of 95% (87 of 92 children), compared with 53% (41 of 78 children) for amodiaquine (difference, 42%; 95% CI, 30%-54%; P<.001). The incidence of adverse events was similar in both groups, and no serious adverse events were attributed to the use of atovaquone/proguanil. Atovaquone/proguanil was found to be highly effective and safe for the treatment of Plasmodium falciparum malaria in infants and young children weighing 5-10 kg in Africa.

To assess the frequency of asymptomatic plasmodial infections in young children living in an area of hyperendemicity, a cohort of 200 children in Gabon was investigated longitudinally. Of 660 cases of Plasmodium falciparum infection, 77% were symptomatic at the time they were identified and only 7% were preceded by an asymptomatic phase of >4 days. Sickle cell trait, glucose-6-phosphate dehydrogenase deficiency, and mutation in the promoter region of tumor necrosis factor (TNF(-376A/-238A)) were significantly associated with asymptomatic P. falciparum infection (P=.03, P=.009, and P<.001, respectively). We conclude that true asymptomatic cases of P. falciparum infection are uncommon in young children and that single measurements or measurements made at long time intervals will lead to a strong underestimation of the incidence of malaria.

ABSTRACT In previous studies, fosmidomycin has been shown to possess activity against Plasmodium falciparum in vitro and in the mouse model. It has a novel mode of action through inhibition of 1-deoxy- d -xylulose 5-phosphate reductoisomerase, an enzyme of the nonmevalonate pathway of isoprenoid biosynthesis, which is absent in humans. In this open-label, uncontrolled trial, the efficacy and safety of fosmidomycin, in an oral dose of 1,200 mg every 8 h for 7 days, were evaluated in the treatment of acute uncomplicated Plasmodium falciparum malaria in 20 adult subjects in Gabon and Thailand. Clinical assessments were performed and thick blood smears were evaluated every 8 h until parasite clearance and resolution of symptoms were achieved; assessments continued at weekly intervals thereafter for the duration of the 28-day followup period. All subjects were clinically and parasitologically cured on day 7 (primary end point). Parasite and fever clearance were rapid, with means of 44 and 41 h, respectively. On day 28, seven out of nine subjects (78%) were cured in Gabon and two out of nine subjects (22%) were cured in Thailand. The drug was well tolerated, although mild gastrointestinal side effects were recorded for five subjects. Analysis of hematological and biochemical parameters showed no clinically significant changes throughout the study. Fosmidomycin is an effective and safe antimalarial drug, although its use as a single agent is restricted by the occurrence of recrudescent infections. However, its role in combination therapy should be explored.

This study evaluated the efficacy and safety of a 3-day course of artesunate (4 mg/kg/day) for asymptomatic Plasmodium malariae infections. The parasitological cure rates on days 7 and 56 in the group treated with artesunate were 100% and 83%, respectively, compared with no cure in the placebo group (P < 0.0001).

Increasing resistance of Plasmodium falciparum to antimalarial drugs presents a major risk factor for people living in endemic areas of tropical Africa. In Lambaréné, Gabon, regular surveillance of chloroquine sensitivity of P. falciparum in vitro has been carried out since 1992 using the WHO standard microtest. Results indicated that from 1994 onwards chloroquine resistance in vitro decreased significantly and that by 2000, about 70% of parasite isolates seemed to be sensitive to chloroquine in vitro. In 2001, we conducted a clinical study to reassess the efficacy of chloroquine in vivo for the treatment of uncomplicated P. falciparum malaria. Twenty-six patients aged 4-15 years were included in this study. Most unexpectedly, the study demonstrated high-grade resistance to chloroquine in vivo (failure rate on day 28 of 100%). As a consequence, tests of parasite susceptibility to chloroquine in vitro were repeated using the same protocol except for the replacement of previously used commercially available predosed WHO culture plates by independently dosed plates. All tested P. falciparum isolates were highly resistant to chloroquine, correlating well with our clinical findings. We concluded that high level resistance of P. falciparum to chloroquine persists in the study area. Neglect or absence of quality controls of essential test material can lead to invalid study results and wrong conclusions and should always be suspected in the case of major fluctuations in the sensitivity patterns of an antimalarial drug in vitro. In addition, our results highlight the supreme value of tests in vivo in providing reliable estimates of the efficacy of an antimalarial in a specific area.

A double-blind, placebo-controlled study was conducted to measure the impact of malaria prophylaxis with atovaquone/proguanil (A-P) on the immunogenicity of vaccines against typhoid fever and cholera, Salmonella serotype Typhi Ty21a and Vibrio cholerae CVD103-HgR, respectively. A total of 330 Gabonese schoolchildren were assigned to receive either A-P or placebo for 12 weeks. Vaccination occurred 3 weeks after the start of prophylaxis, and immunogenicity was assessed 4 weeks after vaccination. The protective efficacy of A-P against Plasmodium falciparum malaria was of 97% (95% confidence interval, 79%-100%). The 2 treatment groups did not differ significantly with regard to changes in antibody titers after vaccination (P=.96 for anti-S. Typhi IgG antibodies, P=.07 for anti-S. Typhi IgA antibodies, and P=.64 for vibriocidal antibodies). The A-P combination was highly effective for malaria prophylaxis, without interfering with the in vivo immunogenicity of CVD103-HgR and Ty21a vaccines, and it could therefore be simultaneously administered with these vaccines.

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.

Background Increasing drug resistance limits the choice of efficacious chemotherapy against Plasmodium falciparum malaria in Africa. Amodiaquine still retains efficacy against P falciparum in many African countries. We assessed the safety, treatment efficacy, and effect on gametocyte carriage of adding artesunate to amodiaquine in three randomised trials in Kenya, Senegal, and Gabon.Methods We enrolled 941 children (400 in Kenya, 321 in Senegal, and 220 in Gabon) who were 10 years or older and who had uncomplicated P falciparum malaria. Patients were randomly assigned amodiaquine (10 mg/kg per day for 3 days) plus artesunate (4 mg/kg per day for 3 days) or amodiaquine (as above) and placebo (for 3 days). The primary endpoints were parasitological cure rates at days 14 and 28. Analysis was by intention to treat and by an evaluability method.Findings Both regimens were well tolerated. Six patients in the amodiaquine-artesunate group and five in the amodiaquine group developed early, drug-induced vomiting, necessitating alternative treatment. By intention-to-treat analysis, the day-14 cure rates for amodiaquine-artesunate versus amodiaquine were: 175/192 (91%) versus 140/188 (74%) in Kenya (Delta=16.7% [95% CI 9.3-24.1], p<0.0001), 148/160 (93%) versus 147/157 (94%) in Senegal (-1.1% [-6.7 to 4.5], p=0.7), and 92/94 (98%) versus 86/96 (90%) in Gabon (8.3% [1.5-15.1], p=0.02). The corresponding rates for day 28 were: 123/180 (68%) versus 75/183 (41%) in Kenya (27.3% [17.5-37.2], p<0.0001), 130/159 (82%) versus 123/156 (79%) in Senegal (2.9% [-5.9 to 11.7], p=0.5), and 80/94 (85%) versus 70/98 (71%) in Gabon (13.7% [2.2-25.2], p=0.02). Similar rates were obtained by evaluability analysis.Interpretation The combination of artesunate and amodiaquine improved treatment efficacy in Gabon and Kenya, and was equivalent in Senegal. Amodiaquine-artesunate is a potential combination for use in Africa. Further investigations to assess the potential effect on the evolution of drug resistance, disease transmission, and safety of amodiaquine-artesunate are warranted.

Semi-immunity against Plasmodium falciparum occurs after many infections. In areas of high malaria transmission, the prevalence of asymptomatic parasite carriers increases with age. We investigated P. falciparum genotypes in a cohort of asymptomatic carriers who were followed until they became symptomatic. Blood spots on filter paper and blood smears were collected daily from 10 children in Lambaréné, Gabon. The parasite genotypes present on successive days were determined by a polymerase chain reaction using the polymorphic region of the merozoite surface antigen-2 for typing. The same parasite genotypes persisted in eight out of ten children and parasite densities were low throughout the asymptomatic phase indicating inhibition of parasite growth. Appearance of symptoms was associated with an increase in parasitemia and appearance of novel parasite genotypes. The results suggest that the parasites causing a clinical episode are those against which a child has not yet mounted an efficient protective immune response.

We describe an age-structured mathematical model of the malaria parasite life cycle that uses clinical observations of peripheral parasitaemia to estimate population dynamics of sequestered parasites, which are hidden from the clinical investigator. First, the model was tested on parasite populations cultured in vitro, and was found to account for ∼72% of the variation in that sub-population of parasites that would have been sequestered in vivo. Next, the model was applied to patients undergoing antimalarial therapy. Using individual data sets we found that although the model fitted the peripheral parasite curves very well, unique solutions for the fit could not be obtained; therefore, robust estimates of sequestered parasite dynamics remained unavailable. We conclude that even given detailed data on individual parasitaemia, estimates of sequestered numbers may be difficult to obtain. However, if data on individuals undergoing similar therapy are collected at equal time intervals, some of these problems may be overcome by estimating specific parameters over groups of patients. In this manner we estimated sequestered parasite density in a group of patients sampled at identical time points following antimalarial treatment. Using this approach we found significant relationships between changes in parasite density, age structure and temperature that were not apparent from the analysis of peripheral parasitaemia only.

Background Tafenoquine is an analogue of primaquine with an improved therapeutic and safety profile. It has a long half-life and activity against liver-stage malaria parasites, so may be useful for chemoprophylaxis. In this randomised, double-blind study we assessed the efficacy and safety of tafenoquine in different doses.Methods 2144 individuals aged 12-20 years living in Lambarene, Gabon, an endemic area for Plasmodium falciparum malaria, were invited to take part. 535 attended, and 426 eligible participants were randomly assigned tafenoquine (250 mg, 125 mg, 62.5 mg, or 31.25 mg) or placebo daily for 3 days. 417 received initial curative treatment with halofantrine, and 410 completed the assigned prophylaxis regimen. During follow-up of 70 days, adverse events were recorded and thick blood smears were examined weekly. The primary and secondary endpoints were the number of individuals with positive blood smears by day 56 and day 77, respectively. Analyses were per-protocol.Findings Eight positive blood smears were recorded by day 56 (four/82 participants in the placebo group; four/79 tafenoquine 31.25 mg group). By day 77, 34 positive blood smears had been recorded (14/82 placebo; 16/79 tafenoquine 31.25 mg; three/86 tafenoquine 62.5 mg; one/79 tafenoquine 125 mg; none/84 tafenoquine 250 mg). Numbers of adverse events did not differ significantly between the treatment groups.Interpretation Tafenoquine is effective and well tolerated. It has the potential to replace currently used drugs for malaria chemoprophylaxis.

Journal Article Genetic diversity of Plasmodium falciparum infections in one family in Lambaréné Get access Michel A. Missinou, Michel A. Missinou 1Department of Parasitology, Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany2Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon Search for other works by this author on: Oxford Academic PubMed Google Scholar Oliver Dangelmaier, Oliver Dangelmaier 1Department of Parasitology, Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany2Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon Search for other works by this author on: Oxford Academic PubMed Google Scholar Jürgen F.J. Kun, Jürgen F.J. Kun ∗ 1Department of Parasitology, Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany ∗Author for conespondence: phone +49 7071 2980240, fax +49 707 1 295 189. juergen.kun@uni-tuebingen.de Search for other works by this author on: Oxford Academic PubMed Google Scholar Peter G. Kremsner Peter G. Kremsner 1Department of Parasitology, Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany2Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 94, Issue 4, July-August 2000, Page 376, https://doi.org/10.1016/S0035-9203(00)90109-3 Published: 01 August 2000 Article history Received: 17 January 2000 Revision received: 20 March 2000 Accepted: 11 April 2000 Published: 01 August 2000