Rachida Tahar - Academia.edu (original) (raw)

Papers by Rachida Tahar

The Journal of Infectious Diseases, Jun 15, 2017

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates the binding and accumulati... more Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates the binding and accumulation of infected erythrocytes (IE) to blood vessels and tissues. Specific interactions have been described between PfEMP1 and human endothelial proteins CD36, intercellular adhesion molecule-1 (ICAM-1), and endothelial protein C receptor (EPCR); however, cytoadhesion patterns typical for pediatric malaria syndromes and the associated PfEMP1 members are still undefined. In a cohort of 94 hospitalized children with malaria, we characterized the binding properties of IE collected on admission, and var gene transcription using quantitative polymerase chain reaction. IE from patients with cerebral malaria were more likely to bind EPCR and ICAM-1 than IE from children with uncomplicated malaria (P = .007). The level of transcripts encoding CIDRα1.4 and CIDRα1.5 domain subclasses was higher in patients with severe disease (P < .05). IE populations exhibiting binding to all 3 receptors had higher levels of transcripts encoding PfEMP1 with CIDRα1.4 and Duffy binding-like (DBL)-β3 domains than parasites, which only bound CD36. These results underpin the significance of EPCR binding in pediatric malaria patients that require hospital admission, and support the notion that complementary receptor interactions of EPCR binding PfEMP1with ICAM-1 amplifies development of severe malaria symptoms.

Acta Tropica, Sep 1, 2004

In Plasmodium vivax, pyrimethamine resistance is associated with amino acid substitutions Ser117A... more In Plasmodium vivax, pyrimethamine resistance is associated with amino acid substitutions Ser117Asn and Ser58Arg in dihydrofolate reductase (DHFR), which correspond to Ser108Asn and Cys59Arg in the Plasmodium falciparum homolog, respectively. Sequence variations within the DHFR domain of 32 P. vivax isolates from Snoul, Cambodia, were analyzed by direct sequencing of polymerase chain reaction (PCR) products. Sequence polymorphisms within the entire DHFR domain were limited to codons 58 and 117 and GGDN tandem repeat units. A large majority (30 of 32) of isolates were characterized to be double mutants (Arg-58 and Asn-117) and associated with the presence of two GGDN repeat units. Only one isolate was of wild-type with three GGDN repeat units, and an additional isolate was of mixed type. Our data suggest that most Cambodian P. vivax isolates display double dhfr mutations associated with pyrimethamine resistance, as in the neighboring countries in Southeast Asia. Further molecular characterization of P. vivax isolates from different endemic areas may be a useful alternative approach to establish the epidemiology of drug-resistant malaria.

Acta Parasitologica, 1995

American Journal of Tropical Medicine and Hygiene, Aug 1, 2007

In vitro pyrimethamine response of Plasmodium falciparum isolates and dihydrofolate reductase (dh... more In vitro pyrimethamine response of Plasmodium falciparum isolates and dihydrofolate reductase (dhfr) gene sequences were analyzed in 2004-2005 and compared with our previous data. Most isolates (n ‫ס‬ 103, all dhfr mutants) had 50% inhibitory concentrations (IC 50 s) Ն 119 nM, and six isolates had low IC 50 s (five wild-type or mixed dhfr, 0.04-1.37 nM; one triple mutant, 6.4 nM). Of 194 isolates, only 7 had the wild-type dhfr and 187 were mutants. The results of the two methods were highly concordant and indicated a significant increase (P < 0.05) in the prevalence of mutant, pyrimethamine-resistant P. falciparum between 1994 and 2005. The addition of probenecid or sulfinpyrazone to pyrimethamine resulted in a slight-to-moderate decrease in the level of in vitro pyrimethamine resistance without rendering the parasites susceptible to pyrimethamine. Analysis of molecular markers may be useful for the long-term surveillance of antifolate-resistant malaria.

American Journal of Tropical Medicine and Hygiene, Jul 1, 2011

American Journal of Tropical Medicine and Hygiene, Sep 1, 2006

In vitro pyrimethamine response of Plasmodium falciparum isolates and dihydrofolate reductase (dh... more In vitro pyrimethamine response of Plasmodium falciparum isolates and dihydrofolate reductase (dhfr) gene sequences were analyzed in 2004-2005 and compared with our previous data. Most isolates (n = 103, all dhfr mutants) had 50% inhibitory concentrations (IC(50)s) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 119 nM, and six isolates had low IC(50)s (five wild-type or mixed dhfr, 0.04-1.37 nM; one triple mutant, 6.4 nM). Of 194 isolates, only 7 had the wild-type dhfr and 187 were mutants. The results of the two methods were highly concordant and indicated a significant increase (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) in the prevalence of mutant, pyrimethamine-resistant P. falciparum between 1994 and 2005. The addition of probenecid or sulfinpyrazone to pyrimethamine resulted in a slight-to-moderate decrease in the level of in vitro pyrimethamine resistance without rendering the parasites susceptible to pyrimethamine. Analysis of molecular markers may be useful for the long-term surveillance of antifolate-resistant malaria.

Acta Tropica, Aug 1, 2007

In vitro pyrimethamine response of Plasmodium falciparum isolates and dihydrofolate reductase (dh... more In vitro pyrimethamine response of Plasmodium falciparum isolates and dihydrofolate reductase (dhfr) gene sequences were analyzed in 2004-2005 and compared with our previous data. Most isolates (n = 103, all dhfr mutants) had 50% inhibitory concentrations (IC(50)s) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 119 nM, and six isolates had low IC(50)s (five wild-type or mixed dhfr, 0.04-1.37 nM; one triple mutant, 6.4 nM). Of 194 isolates, only 7 had the wild-type dhfr and 187 were mutants. The results of the two methods were highly concordant and indicated a significant increase (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) in the prevalence of mutant, pyrimethamine-resistant P. falciparum between 1994 and 2005. The addition of probenecid or sulfinpyrazone to pyrimethamine resulted in a slight-to-moderate decrease in the level of in vitro pyrimethamine resistance without rendering the parasites susceptible to pyrimethamine. Analysis of molecular markers may be useful for the long-term surveillance of antifolate-resistant malaria.

Emerging Infectious Diseases, Feb 1, 2019

The Journal of Infectious Diseases, Aug 1, 2000

Mutations in dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) are associated wi... more Mutations in dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) are associated with in vitro resistance to sulfadoxine and pyrimethamine, respectively. The response of 75 patients to sulfadoxine-pyrimethamine was determined, and the genes of the corresponding Plasmodium falciparum isolates were sequenced. Of 12 different unmixed allelic combinations, the triple dhfr mutation Asn-108/Arg-59/Ile-51 was observed in all patients responding with early treatment failure. Some, but not all, patients with an adequate clinical response also harbored isolates with the triple dhfr mutation. Higher initial parasitemia and fever distinguished these 2 patient groups. The dhps genotype apparently had no influence on the clinical outcome. The other dhfr alleles with 1 or 2 mutations and the wild-type allele were found in patients with an adequate clinical response. The triple dhfr mutation is one of the genetic determinants associated with in vivo resistance to sulfadoxine-pyrimethamine. Since the rapid spread of chloroquine resistance in Asia and South America in the 1960s and 1970s, sulfadoxine-pyrimethamine has been one of the most important second-line drugs for the treatment of chloroquine-resistant Plasmodium falciparum infections [1]. The extensive use of sulfadoxine-pyrimethamine has led to the selection of resistant strains and declining efficacy to the point that this drug is no longer recommended in some areas endemic for the disease. In Africa, chloroquine resistance emerged much later than in other endemic areas. Chloroquine is still the first-line drug in central and West Africa, and sulfadoxine-pyrimethamine usually is re

Malaria Journal, Apr 15, 2023

Background The human host elicits specific immune responses after exposure to various life stages... more Background The human host elicits specific immune responses after exposure to various life stages of the malaria parasite as well as components of mosquito saliva injected into the host during a mosquito bite. This study describes differences in IgG responses against antigens derived from the sporozoite (PfCSP), asexual stage parasite (PfEBA175) and the gametocyte (Pfs230), in addition to an Anopheles gambiae salivary gland antigen (gSG6-P1), in two communities in Ghana with similar blood stage malaria parasite prevalence. Methods This study used archived plasma samples collected from an earlier cross-sectional study that enrolled volunteers aged from 6 months to 70 years from Simiw, peri-urban community (N = 347) and Obom, rural community (N = 291). An archived thick and thin blood smear for microscopy was used for the estimation of Plasmodium parasite density and species and DNA extraction from blood spots and P. falciparum confirmation was performed using PCR. This study used the stored plasma samples to determine IgG antibody levels to P. falciparum and Anopheles salivary antigens using indirect ELISA. Results Individuals from Simiw had significantly higher levels of IgG against mosquito gSG6-P1 [median (95%CI)] [2.590 (2.452-2.783) ng/mL] compared to those from Obom [2.119 (1.957-2.345) ng/mL], p < 0.0001. Both IgG responses against Pfs230proC (p = 0.0006), and PfCSP (p = 0.002) were significantly lower in volunteers from Simiw compared to the participants from Obom. The seroprevalence of PfEBA-175.5R (p = 0.8613), gSG6-P1 (p = 0.0704), PfCSP (p = 0.7798) IgG were all similar in Obom and Simiw. However, Pfs230 seroprevalence was significantly higher at Obom compared to Simiw (p = 0.0006). Spearman correlation analysis showed no significant association between IgG responses against gSG6-P1, PfCSP, Pfs230proC and PfEBA-175.5R and parasite density at both Obom and Simiw (p > 0.05). Conclusion In conclusion, the study showed that participants from Simiw had higher concentrations of circulating gSG6-P1 IgG antibodies but lower concentrations of P. falciparum antibodies, PfCSP IgG and Pfs230proC IgG compared to participants from Obom.

Molecular and Biochemical Parasitology, Sep 1, 1997

Malaria Research and Treatment, Dec 17, 2012

The Republic of the Congo adopted artemisinin-based combination therapies (ACTs) in 2006: artesun... more The Republic of the Congo adopted artemisinin-based combination therapies (ACTs) in 2006: artesunate-amodiaquine and artemether-lumefantrine as the first-line and second-line drugs, respectively. The baseline efficacy of artemether-lumefantrine was evaluated between March and July 2006 in Brazzaville, the capital city of Congo. Seventy-seven children aged between 6 months and 10 years were enrolled in a nonrandomized study. The children were treated under supervision with 6 doses of artemetherlumefantrine and followed up for 28 days in accordance with the 2003 World Health Organization guideline. Pretreatment (i.e., day 0) and recrudescent Plasmodium falciparum isolates between day 14 and day 28 were compared by the polymerase chain reaction to distinguish between true recrudescence and reinfection. The overall cure rate on day 28 was 96.9% after PCR correction. Reported adverse effects included pruritus and dizziness. Artemether-lumefantrine was highly efficacious in Brazzaville.

Malaria Journal, Nov 8, 2018

Background: Plasmodium vivax is the predominant malaria species in northern Mauritania. Molecular... more Background: Plasmodium vivax is the predominant malaria species in northern Mauritania. Molecular data on P. vivax isolates circulating in West Africa are scarce. The present study analysed molecular markers associated with resistance to antifolates (Pvdhfr and Pvdhps), chloroquine (Pvmdr1), and artemisinin (Pvk12) in P. vivax isolates collected in two cities located in the Saharan zone of Mauritania. Methods: Blood samples were obtained from P. vivax-infected patients recruited for chloroquine therapeutic efficacy study in 2013 and febrile patients spontaneously consulting health facilities in Nouakchott and Atar in 2015-2016.

American Journal of Tropical Medicine and Hygiene, Aug 1, 2007

The in vitro activities of fosmidomycin derivatives, chloroquine, and pyrimethamine were assessed... more The in vitro activities of fosmidomycin derivatives, chloroquine, and pyrimethamine were assessed by the radioisotopic assay in clinical isolates of Plasmodium falciparum. In a series of experiments with RPMI 1640 medium-10% fetal bovine serum, the geometric mean 50% inhibitory concentrations (IC 50 s) (n ‫ס‬ 34) for fosmidomycin and FR900098 were 301 nM and 118 nM, respectively. In another series of experiments, the geometric mean IC 50 s (n ‫ס‬ 33) for fosmidomycin and TH II46 were 413 nM and 249 nM, respectively. The IC 50 s were 2-3 times lower with RPMI-10% fetal bovine serum than the IC 50 s obtained with RPMI-10% human serum. FR900098 and TH II46 were 2.6 and 1.7 times more potent, respectively, than fosmidomycin. There was no correlation between chloroquine or pyrimethamine and fosmidomycin, which suggested the absence of in vitro cross-resistance. Sequence analysis showed five amino acid substitutions, but their possible relationship with the response to fosmidomycin is not clear. Fosmidomycin derivatives are promising candidates for further development.

Molecular and Cellular Probes, Dec 1, 1997

A polymerase chain reaction (PCR) assay was developed for the specific detection of Plasmodium ov... more A polymerase chain reaction (PCR) assay was developed for the specific detection of Plasmodium ovale, one of the four malaria parasites that infect humans. On the basis of sequence variation of the Plasmodium 18S ribosomal RNA (rRNA) gene, oligonucleotide primers for PCR were designed to amplify various fragments of the P. ovale gene. Using a recombinant plasmid with the complete P. ovale 18S rRNA gene as target, 59 primer combinations were tested so that at least one of the pairs was species-specific while the other primer was either genus conserved or P. ovale species-specific. Three primer pairs yielding DNA fragments at stringent conditions were further tested against genomic DNA of four human malaria species. This approach yielded P. ovale species-specific primer pairs that may be useful for further field testing.

Malaria Journal, Aug 3, 2017

Background: Artemisinin-based combination therapy (ACT) and novel drug combinations are available... more Background: Artemisinin-based combination therapy (ACT) and novel drug combinations are available and used in African countries to treat uncomplicated malaria. Network meta-analysis methods are rarely and poorly applied for the comparison of their efficacies. This method was applied on a set of randomized controlled trials to illustrate its usefulness. Methods: A literature review available in Pubmed was conducted in July 2016. Eligible studies, conducted in sub-Saharan Africa, published between 2002 and 2016, focused on randomized controlled trials of at least two artemisinin-based combinations to treat uncomplicated malaria in children and adults. Agglomerate data were: the number of PCR-corrected adequate clinical and parasitological response (ACPR) on day 28, used as the primary endpoint in all interventions, the number of participants and the list of treatments. A Bayesian random effect meta-analysis using a binary outcome was the method to compare the efficacy. Ranking measure was used to obtain a hierarchy of the competing interventions. Results: In total, 76 articles were included; 13 treatment regimens were involved and tested in 36,001 patients. Using artemether-lumefantrine (AL) as the common comparator for the entire network, 12 relative treatment effects were estimated and indirect comparisons were obtained. Dihydroartemisinin-piperaquine (DHAP) was shown to be more effective than AL (odds ratio [OR] = 1.92; 95% CI 1.30-2.82; 19,163 patients), ASAQ (OR = 1.70; 95% CI 1.10-2.64; 14,433 patients), and amodiaquine-sulfadoxine-pyrimethamine (AQSP): OR = 2.20; 95% CI 1.21-3.96; 8863 patients. Artesunate-amodiaquine (ASAQ) was comparable to AL (OR = 1.11; 95% CI 0.84-1.45; 21,235 patients). No significant difference was found between artesunate and mefloquine (ASMQ) and AL (OR = 1.20; 95% CI = 0.52-2.8; 13,824 participants). According to treatment ranking, among the WHO-recommended ACT medicines, DHAP was shown to be the most efficacious. Conclusions: Based on the available evidence, this study demonstrated the superiority of DHAP among currently recommended artemisinin-based combinations. The application of the methods described here may be helpful to gain better understanding of treatment efficacy and improve future decisions. However, more data are needed to allow robust conclusions about the results in comparison with novel drugs. Further surveillance of the efficacy of anti-malarial drugs and clinical trials are needed to closely follow the evolution of the epidemiology of drug-resistant malaria in Africa.

The Journal of Infectious Diseases, Nov 25, 2014

Transactions of The Royal Society of Tropical Medicine and Hygiene, Jul 1, 1997

Parasite, Mar 1, 1995

T h e a d j u s t m e n t o f t h e s c h i z o g o n i c c y c l e o f P l a s m o d iu m c h a ... more T h e a d j u s t m e n t o f t h e s c h i z o g o n i c c y c l e o f P l a s m o d iu m c h a b a u d i c h a b a u d i in t h e b l o o d TO THE CIRCADIAN RHYTHM OF THE HOST

Malaria Journal, Mar 27, 2017

Background: Chloroquine had been used extensively during the last five decades in Cameroon. Its d... more Background: Chloroquine had been used extensively during the last five decades in Cameroon. Its decreasing clinical effectiveness, supported by high proportions of clinical isolates carrying the mutant pfcrt haplotype (CVIET), led the health authorities to resort to amodiaquine monotherapy in 2002 and artemisinin-based combination therapy (ACT) in 2004 (artesunate-amodiaquine, with artemether-lumefantrine as an alternative since 2006) as the first-line treatment of uncomplicated malaria. The aim of the present study was to investigate whether the withdrawal of chloroquine was associated with a reduction in pfcrt mutant parasite population and reemergence of chloroquinesensitive parasites in southeastern Cameroon between 2003 and 2012. Methods: The frequency of pfcrt haplotypes at positions 72-76 in Plasmodium falciparum isolates collected from individuals in 2003 and 2012 in southeastern Cameroon was determined by sequence specific oligonucleotide probes-enzyme linked immunosorbent assay (SSOP-ELISA). Results: The proportions of parasites carrying the mutant haplotype CVIET and the wild-type CVMNK were 53.0 and 28.0% in 2003, respectively. The proportion of the mutant haplotype in samples collected 9 years later decreased to 25.3% whereas the proportion of parasites carrying the wild-type CVMNK haplotype was 53.7%. Conclusions: Even though the proportion of chloroquine-sensitive parasites seems to be increasing in southeastern Cameroon, a reintroduction of chloroquine cannot be recommended at present in Cameroon. The current national anti-malarial drug policy should be implemented and reinforced to combat drug-resistant malaria.

The Journal of Infectious Diseases, Jun 15, 2017

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates the binding and accumulati... more Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates the binding and accumulation of infected erythrocytes (IE) to blood vessels and tissues. Specific interactions have been described between PfEMP1 and human endothelial proteins CD36, intercellular adhesion molecule-1 (ICAM-1), and endothelial protein C receptor (EPCR); however, cytoadhesion patterns typical for pediatric malaria syndromes and the associated PfEMP1 members are still undefined. In a cohort of 94 hospitalized children with malaria, we characterized the binding properties of IE collected on admission, and var gene transcription using quantitative polymerase chain reaction. IE from patients with cerebral malaria were more likely to bind EPCR and ICAM-1 than IE from children with uncomplicated malaria (P = .007). The level of transcripts encoding CIDRα1.4 and CIDRα1.5 domain subclasses was higher in patients with severe disease (P &amp;amp;lt; .05). IE populations exhibiting binding to all 3 receptors had higher levels of transcripts encoding PfEMP1 with CIDRα1.4 and Duffy binding-like (DBL)-β3 domains than parasites, which only bound CD36. These results underpin the significance of EPCR binding in pediatric malaria patients that require hospital admission, and support the notion that complementary receptor interactions of EPCR binding PfEMP1with ICAM-1 amplifies development of severe malaria symptoms.

Acta Tropica, Sep 1, 2004

In Plasmodium vivax, pyrimethamine resistance is associated with amino acid substitutions Ser117A... more In Plasmodium vivax, pyrimethamine resistance is associated with amino acid substitutions Ser117Asn and Ser58Arg in dihydrofolate reductase (DHFR), which correspond to Ser108Asn and Cys59Arg in the Plasmodium falciparum homolog, respectively. Sequence variations within the DHFR domain of 32 P. vivax isolates from Snoul, Cambodia, were analyzed by direct sequencing of polymerase chain reaction (PCR) products. Sequence polymorphisms within the entire DHFR domain were limited to codons 58 and 117 and GGDN tandem repeat units. A large majority (30 of 32) of isolates were characterized to be double mutants (Arg-58 and Asn-117) and associated with the presence of two GGDN repeat units. Only one isolate was of wild-type with three GGDN repeat units, and an additional isolate was of mixed type. Our data suggest that most Cambodian P. vivax isolates display double dhfr mutations associated with pyrimethamine resistance, as in the neighboring countries in Southeast Asia. Further molecular characterization of P. vivax isolates from different endemic areas may be a useful alternative approach to establish the epidemiology of drug-resistant malaria.

Acta Parasitologica, 1995

American Journal of Tropical Medicine and Hygiene, Aug 1, 2007

In vitro pyrimethamine response of Plasmodium falciparum isolates and dihydrofolate reductase (dh... more In vitro pyrimethamine response of Plasmodium falciparum isolates and dihydrofolate reductase (dhfr) gene sequences were analyzed in 2004-2005 and compared with our previous data. Most isolates (n ‫ס‬ 103, all dhfr mutants) had 50% inhibitory concentrations (IC 50 s) Ն 119 nM, and six isolates had low IC 50 s (five wild-type or mixed dhfr, 0.04-1.37 nM; one triple mutant, 6.4 nM). Of 194 isolates, only 7 had the wild-type dhfr and 187 were mutants. The results of the two methods were highly concordant and indicated a significant increase (P < 0.05) in the prevalence of mutant, pyrimethamine-resistant P. falciparum between 1994 and 2005. The addition of probenecid or sulfinpyrazone to pyrimethamine resulted in a slight-to-moderate decrease in the level of in vitro pyrimethamine resistance without rendering the parasites susceptible to pyrimethamine. Analysis of molecular markers may be useful for the long-term surveillance of antifolate-resistant malaria.

American Journal of Tropical Medicine and Hygiene, Jul 1, 2011

American Journal of Tropical Medicine and Hygiene, Sep 1, 2006

In vitro pyrimethamine response of Plasmodium falciparum isolates and dihydrofolate reductase (dh... more In vitro pyrimethamine response of Plasmodium falciparum isolates and dihydrofolate reductase (dhfr) gene sequences were analyzed in 2004-2005 and compared with our previous data. Most isolates (n = 103, all dhfr mutants) had 50% inhibitory concentrations (IC(50)s) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 119 nM, and six isolates had low IC(50)s (five wild-type or mixed dhfr, 0.04-1.37 nM; one triple mutant, 6.4 nM). Of 194 isolates, only 7 had the wild-type dhfr and 187 were mutants. The results of the two methods were highly concordant and indicated a significant increase (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) in the prevalence of mutant, pyrimethamine-resistant P. falciparum between 1994 and 2005. The addition of probenecid or sulfinpyrazone to pyrimethamine resulted in a slight-to-moderate decrease in the level of in vitro pyrimethamine resistance without rendering the parasites susceptible to pyrimethamine. Analysis of molecular markers may be useful for the long-term surveillance of antifolate-resistant malaria.

Acta Tropica, Aug 1, 2007

In vitro pyrimethamine response of Plasmodium falciparum isolates and dihydrofolate reductase (dh... more In vitro pyrimethamine response of Plasmodium falciparum isolates and dihydrofolate reductase (dhfr) gene sequences were analyzed in 2004-2005 and compared with our previous data. Most isolates (n = 103, all dhfr mutants) had 50% inhibitory concentrations (IC(50)s) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 119 nM, and six isolates had low IC(50)s (five wild-type or mixed dhfr, 0.04-1.37 nM; one triple mutant, 6.4 nM). Of 194 isolates, only 7 had the wild-type dhfr and 187 were mutants. The results of the two methods were highly concordant and indicated a significant increase (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) in the prevalence of mutant, pyrimethamine-resistant P. falciparum between 1994 and 2005. The addition of probenecid or sulfinpyrazone to pyrimethamine resulted in a slight-to-moderate decrease in the level of in vitro pyrimethamine resistance without rendering the parasites susceptible to pyrimethamine. Analysis of molecular markers may be useful for the long-term surveillance of antifolate-resistant malaria.

Emerging Infectious Diseases, Feb 1, 2019

The Journal of Infectious Diseases, Aug 1, 2000

Mutations in dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) are associated wi... more Mutations in dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) are associated with in vitro resistance to sulfadoxine and pyrimethamine, respectively. The response of 75 patients to sulfadoxine-pyrimethamine was determined, and the genes of the corresponding Plasmodium falciparum isolates were sequenced. Of 12 different unmixed allelic combinations, the triple dhfr mutation Asn-108/Arg-59/Ile-51 was observed in all patients responding with early treatment failure. Some, but not all, patients with an adequate clinical response also harbored isolates with the triple dhfr mutation. Higher initial parasitemia and fever distinguished these 2 patient groups. The dhps genotype apparently had no influence on the clinical outcome. The other dhfr alleles with 1 or 2 mutations and the wild-type allele were found in patients with an adequate clinical response. The triple dhfr mutation is one of the genetic determinants associated with in vivo resistance to sulfadoxine-pyrimethamine. Since the rapid spread of chloroquine resistance in Asia and South America in the 1960s and 1970s, sulfadoxine-pyrimethamine has been one of the most important second-line drugs for the treatment of chloroquine-resistant Plasmodium falciparum infections [1]. The extensive use of sulfadoxine-pyrimethamine has led to the selection of resistant strains and declining efficacy to the point that this drug is no longer recommended in some areas endemic for the disease. In Africa, chloroquine resistance emerged much later than in other endemic areas. Chloroquine is still the first-line drug in central and West Africa, and sulfadoxine-pyrimethamine usually is re

Malaria Journal, Apr 15, 2023

Background The human host elicits specific immune responses after exposure to various life stages... more Background The human host elicits specific immune responses after exposure to various life stages of the malaria parasite as well as components of mosquito saliva injected into the host during a mosquito bite. This study describes differences in IgG responses against antigens derived from the sporozoite (PfCSP), asexual stage parasite (PfEBA175) and the gametocyte (Pfs230), in addition to an Anopheles gambiae salivary gland antigen (gSG6-P1), in two communities in Ghana with similar blood stage malaria parasite prevalence. Methods This study used archived plasma samples collected from an earlier cross-sectional study that enrolled volunteers aged from 6 months to 70 years from Simiw, peri-urban community (N = 347) and Obom, rural community (N = 291). An archived thick and thin blood smear for microscopy was used for the estimation of Plasmodium parasite density and species and DNA extraction from blood spots and P. falciparum confirmation was performed using PCR. This study used the stored plasma samples to determine IgG antibody levels to P. falciparum and Anopheles salivary antigens using indirect ELISA. Results Individuals from Simiw had significantly higher levels of IgG against mosquito gSG6-P1 [median (95%CI)] [2.590 (2.452-2.783) ng/mL] compared to those from Obom [2.119 (1.957-2.345) ng/mL], p < 0.0001. Both IgG responses against Pfs230proC (p = 0.0006), and PfCSP (p = 0.002) were significantly lower in volunteers from Simiw compared to the participants from Obom. The seroprevalence of PfEBA-175.5R (p = 0.8613), gSG6-P1 (p = 0.0704), PfCSP (p = 0.7798) IgG were all similar in Obom and Simiw. However, Pfs230 seroprevalence was significantly higher at Obom compared to Simiw (p = 0.0006). Spearman correlation analysis showed no significant association between IgG responses against gSG6-P1, PfCSP, Pfs230proC and PfEBA-175.5R and parasite density at both Obom and Simiw (p > 0.05). Conclusion In conclusion, the study showed that participants from Simiw had higher concentrations of circulating gSG6-P1 IgG antibodies but lower concentrations of P. falciparum antibodies, PfCSP IgG and Pfs230proC IgG compared to participants from Obom.

Molecular and Biochemical Parasitology, Sep 1, 1997

Malaria Research and Treatment, Dec 17, 2012

The Republic of the Congo adopted artemisinin-based combination therapies (ACTs) in 2006: artesun... more The Republic of the Congo adopted artemisinin-based combination therapies (ACTs) in 2006: artesunate-amodiaquine and artemether-lumefantrine as the first-line and second-line drugs, respectively. The baseline efficacy of artemether-lumefantrine was evaluated between March and July 2006 in Brazzaville, the capital city of Congo. Seventy-seven children aged between 6 months and 10 years were enrolled in a nonrandomized study. The children were treated under supervision with 6 doses of artemetherlumefantrine and followed up for 28 days in accordance with the 2003 World Health Organization guideline. Pretreatment (i.e., day 0) and recrudescent Plasmodium falciparum isolates between day 14 and day 28 were compared by the polymerase chain reaction to distinguish between true recrudescence and reinfection. The overall cure rate on day 28 was 96.9% after PCR correction. Reported adverse effects included pruritus and dizziness. Artemether-lumefantrine was highly efficacious in Brazzaville.

Malaria Journal, Nov 8, 2018

Background: Plasmodium vivax is the predominant malaria species in northern Mauritania. Molecular... more Background: Plasmodium vivax is the predominant malaria species in northern Mauritania. Molecular data on P. vivax isolates circulating in West Africa are scarce. The present study analysed molecular markers associated with resistance to antifolates (Pvdhfr and Pvdhps), chloroquine (Pvmdr1), and artemisinin (Pvk12) in P. vivax isolates collected in two cities located in the Saharan zone of Mauritania. Methods: Blood samples were obtained from P. vivax-infected patients recruited for chloroquine therapeutic efficacy study in 2013 and febrile patients spontaneously consulting health facilities in Nouakchott and Atar in 2015-2016.

American Journal of Tropical Medicine and Hygiene, Aug 1, 2007

The in vitro activities of fosmidomycin derivatives, chloroquine, and pyrimethamine were assessed... more The in vitro activities of fosmidomycin derivatives, chloroquine, and pyrimethamine were assessed by the radioisotopic assay in clinical isolates of Plasmodium falciparum. In a series of experiments with RPMI 1640 medium-10% fetal bovine serum, the geometric mean 50% inhibitory concentrations (IC 50 s) (n ‫ס‬ 34) for fosmidomycin and FR900098 were 301 nM and 118 nM, respectively. In another series of experiments, the geometric mean IC 50 s (n ‫ס‬ 33) for fosmidomycin and TH II46 were 413 nM and 249 nM, respectively. The IC 50 s were 2-3 times lower with RPMI-10% fetal bovine serum than the IC 50 s obtained with RPMI-10% human serum. FR900098 and TH II46 were 2.6 and 1.7 times more potent, respectively, than fosmidomycin. There was no correlation between chloroquine or pyrimethamine and fosmidomycin, which suggested the absence of in vitro cross-resistance. Sequence analysis showed five amino acid substitutions, but their possible relationship with the response to fosmidomycin is not clear. Fosmidomycin derivatives are promising candidates for further development.

Molecular and Cellular Probes, Dec 1, 1997

A polymerase chain reaction (PCR) assay was developed for the specific detection of Plasmodium ov... more A polymerase chain reaction (PCR) assay was developed for the specific detection of Plasmodium ovale, one of the four malaria parasites that infect humans. On the basis of sequence variation of the Plasmodium 18S ribosomal RNA (rRNA) gene, oligonucleotide primers for PCR were designed to amplify various fragments of the P. ovale gene. Using a recombinant plasmid with the complete P. ovale 18S rRNA gene as target, 59 primer combinations were tested so that at least one of the pairs was species-specific while the other primer was either genus conserved or P. ovale species-specific. Three primer pairs yielding DNA fragments at stringent conditions were further tested against genomic DNA of four human malaria species. This approach yielded P. ovale species-specific primer pairs that may be useful for further field testing.

Malaria Journal, Aug 3, 2017

Background: Artemisinin-based combination therapy (ACT) and novel drug combinations are available... more Background: Artemisinin-based combination therapy (ACT) and novel drug combinations are available and used in African countries to treat uncomplicated malaria. Network meta-analysis methods are rarely and poorly applied for the comparison of their efficacies. This method was applied on a set of randomized controlled trials to illustrate its usefulness. Methods: A literature review available in Pubmed was conducted in July 2016. Eligible studies, conducted in sub-Saharan Africa, published between 2002 and 2016, focused on randomized controlled trials of at least two artemisinin-based combinations to treat uncomplicated malaria in children and adults. Agglomerate data were: the number of PCR-corrected adequate clinical and parasitological response (ACPR) on day 28, used as the primary endpoint in all interventions, the number of participants and the list of treatments. A Bayesian random effect meta-analysis using a binary outcome was the method to compare the efficacy. Ranking measure was used to obtain a hierarchy of the competing interventions. Results: In total, 76 articles were included; 13 treatment regimens were involved and tested in 36,001 patients. Using artemether-lumefantrine (AL) as the common comparator for the entire network, 12 relative treatment effects were estimated and indirect comparisons were obtained. Dihydroartemisinin-piperaquine (DHAP) was shown to be more effective than AL (odds ratio [OR] = 1.92; 95% CI 1.30-2.82; 19,163 patients), ASAQ (OR = 1.70; 95% CI 1.10-2.64; 14,433 patients), and amodiaquine-sulfadoxine-pyrimethamine (AQSP): OR = 2.20; 95% CI 1.21-3.96; 8863 patients. Artesunate-amodiaquine (ASAQ) was comparable to AL (OR = 1.11; 95% CI 0.84-1.45; 21,235 patients). No significant difference was found between artesunate and mefloquine (ASMQ) and AL (OR = 1.20; 95% CI = 0.52-2.8; 13,824 participants). According to treatment ranking, among the WHO-recommended ACT medicines, DHAP was shown to be the most efficacious. Conclusions: Based on the available evidence, this study demonstrated the superiority of DHAP among currently recommended artemisinin-based combinations. The application of the methods described here may be helpful to gain better understanding of treatment efficacy and improve future decisions. However, more data are needed to allow robust conclusions about the results in comparison with novel drugs. Further surveillance of the efficacy of anti-malarial drugs and clinical trials are needed to closely follow the evolution of the epidemiology of drug-resistant malaria in Africa.

The Journal of Infectious Diseases, Nov 25, 2014

Transactions of The Royal Society of Tropical Medicine and Hygiene, Jul 1, 1997

Parasite, Mar 1, 1995

T h e a d j u s t m e n t o f t h e s c h i z o g o n i c c y c l e o f P l a s m o d iu m c h a ... more T h e a d j u s t m e n t o f t h e s c h i z o g o n i c c y c l e o f P l a s m o d iu m c h a b a u d i c h a b a u d i in t h e b l o o d TO THE CIRCADIAN RHYTHM OF THE HOST

Malaria Journal, Mar 27, 2017

Background: Chloroquine had been used extensively during the last five decades in Cameroon. Its d... more Background: Chloroquine had been used extensively during the last five decades in Cameroon. Its decreasing clinical effectiveness, supported by high proportions of clinical isolates carrying the mutant pfcrt haplotype (CVIET), led the health authorities to resort to amodiaquine monotherapy in 2002 and artemisinin-based combination therapy (ACT) in 2004 (artesunate-amodiaquine, with artemether-lumefantrine as an alternative since 2006) as the first-line treatment of uncomplicated malaria. The aim of the present study was to investigate whether the withdrawal of chloroquine was associated with a reduction in pfcrt mutant parasite population and reemergence of chloroquinesensitive parasites in southeastern Cameroon between 2003 and 2012. Methods: The frequency of pfcrt haplotypes at positions 72-76 in Plasmodium falciparum isolates collected from individuals in 2003 and 2012 in southeastern Cameroon was determined by sequence specific oligonucleotide probes-enzyme linked immunosorbent assay (SSOP-ELISA). Results: The proportions of parasites carrying the mutant haplotype CVIET and the wild-type CVMNK were 53.0 and 28.0% in 2003, respectively. The proportion of the mutant haplotype in samples collected 9 years later decreased to 25.3% whereas the proportion of parasites carrying the wild-type CVMNK haplotype was 53.7%. Conclusions: Even though the proportion of chloroquine-sensitive parasites seems to be increasing in southeastern Cameroon, a reintroduction of chloroquine cannot be recommended at present in Cameroon. The current national anti-malarial drug policy should be implemented and reinforced to combat drug-resistant malaria.