Background. Usefulness of sulfadoxine-pyrimethamine as first-line therapy for uncomplicated Plasmodium falciparum malaria and intermittent preventive treatment in pregnancy throughout sub-Saharan ...Africa is compromised by the spread of dhfr alleles associated with pyrimethamine resistance. A predominant haplotype associated with the N51I+C59R+S108N triple-mutant dhfr allele has been reported recently in 4 African countries. A more comprehensive picture of the evolution of this mutant allele in Africa is lacking. Methods. Seventy-five P. falciparum isolates carrying the wild-type dhfr allele and 204 carrying the triplemutant dhfr allele from 11 African countries were selected. The genetic diversity of the chromosomes bearing these alleles was analyzed with 4 microsatellite markers closely linked to the dhfr gene. Results. Seventy-three different 4-locus haplotypes carrying the wild-type dhfr allele were found. By contrast, 175 (85%) of 204 isolates carrying the triple-mutant dhfr allele shared a unique haplotype, identical to the one identified in Thailand. For the remaining triple-mutant isolates and one isolate with the quadruple-mutant dhfr allele (N51I+C59R+S108N+I164L), haplotypes were closely related to the predominant haplotype by mutation or recombination. Conclusions. Migration of parasites carrying an ancestral triple-mutant dhfr allele drives the spread of dhfr alleles associated with pyrimethamine resistance throughout West and Central Africa.
Mutations in the Plasmodium falciparum K13-propeller domain have recently been shown to be important determinants of artemisinin resistance in Southeast Asia. This study investigated the prevalence ...of K13-propeller polymorphisms across sub-Saharan Africa. A total of 1212 P. falciparum samples collected from 12 countries were sequenced. None of the K13-propeller mutations previously reported in Southeast Asia were found, but 22 unique mutations were detected, of which 7 were nonsynonymous. Alíele frequencies ranged between 1% and 3%. Three mutations were observed in > 1 country, and the A578S was present in parasites from 5 countries. This study provides the baseline prevalence of K13-propeller mutations in sub-Saharan Africa.
Understanding genomic variation and population structure of
across Africa is necessary to sustain progress toward malaria elimination. Genome clustering of 2263
isolates from 24 malaria-endemic ...settings in 15 African countries identified major western, central, and eastern ancestries, plus a highly divergent Ethiopian population. Ancestry aligned to these regional blocs, overlapping with both the parasite's origin and with historical human migration. The parasite populations are interbred and shared genomic haplotypes, especially across drug resistance loci, which showed the strongest recent identity-by-descent between populations. A recent signature of selection on chromosome 12 with candidate resistance loci against artemisinin derivatives was evident in Ghana and Malawi. Such selection and the emerging substructure may affect treatment-based intervention strategies against
malaria.
Artemether-lumefantrine (AL) and artesunate-amodiaquine are first-line treatment for uncomplicated malaria in many endemic countries, including Mali. Dihydroartemisinin-piperaquine (DHA-PQ) is also ...an alternative first-line artemisinin-based combination therapy, but only few data are available on DHA-PQ efficacy in sub-Saharan Africa. The main aim of this study was to compare clinical efficacy of DHA-PQ versus AL, using the World Health Organization (WHO) 42-day in vivo protocol.
The efficacy of three-dose regimens of DHA-PQ was compared to AL combination in a randomized, comparative open label trial using the WHO 42-day follow-up protocol from 2013 to 2015 in Doneguebougou and Torodo, Mali. The primary endpoint was to access the PCR-corrected Adequate Clinical and Parasitological Responses at day 28.
A total of 317 uncomplicated malaria patients were enrolled, with 159 in DHA-PQ arm and 158 in AL arm. The parasite positivity rate decreased from 68.4% (95% CI 60.5-75.5) on day 1 to 3.8% (95% CI 1.4-8.1) on day 2 for DHA-PQ and 79.8% (95% CI 72.3-85.7) on day 1 to 9.5% (95% CI 5.4-15.2) on day 2 for AL, (p = 0.04). There was a significant difference in the uncorrected ACPR between DHA-PQ and AL, both at 28-day and 42-day follow-up with 97.4% (95% CI 93.5-99.3) in DHA-PQ vs 84.5% (95% CI 77.8-89.8) in AL (p < 0.001) and 94.2% (95% CI 89.3-97.3) in DHA-PQ vs 73.4% (95% CI 65.7-80.2) in AL, respectively (p < 0.001). After molecular correction, there was no significant difference in ACPRc between DHA-PQ and AL, both at the 28-day and 42-day follow-up with 99.4% (95% CI 96.5-100) in DHA-PQ versus 98.1% (95% CI 94.5-99.6) in AL (p = 0.3) and 99.3% (95% CI 96.5-100) in DHA-PQ vs 97.4% (95% CI 93.5-99.3) in AL (p = 0.2). There was no significant difference between DHA-PQ and AL in QTc prolongation 12.1% vs 7%, respectively (p = 0.4).
The results showed that dihydroartemisinin-piperaquine and artemether-lumefantrine were clinically efficacious on Plasmodium falciparum parasites in Mali.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Artemisinin-based combination therapy is the recommended first-line treatment for uncomplicated falciparum malaria worldwide. However, recent studies conducted in Mali showed an increased frequency ...of recurrent parasitaemia following artemether-lumefantrine (AL) treatment.
Study samples were collected during a large WANECAM study. Ex-vivo Plasmodium falciparum sensitivity to artemether and lumefantrine was assessed using the tritiated hypoxanthine-based assay. The prevalence of molecular markers of anti-malarial drug resistance (pfcrt K76T, pfmdr1 N86Y and K13-propeller) were measured by PCR and/or sequencing.
Overall 61 samples were successfully analysed in ex vivo studies. Mean IC
s increased significantly between baseline and recurrent parasites for both artemether (1.6 nM vs 3.2 nM, p < 0.001) and lumefantrine (1.4 nM vs 3.4 nM, p = 0.004). Wild type Pfmdr1 N86 allele was selected after treatment (71 vs 91%, 112 of 158 vs 95 of 105, p < 0.001) but not the wild type pfcrt K76 variant (23.5 vs 24.8%, 40 of 170 vs 26 of 105, p = 0.9). Three non-synonymous K13-propeller SNPs (A522C, A578S, and G638R) were found with allele frequencies <2%.
Malian post-AL P. falciparum isolates were less susceptible to artemether and lumefantrine than baseline isolates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
One of the key obstacles to malaria elimination is largely attributed to Plasmodium vivax's ability to form resilient hypnozoites in the host liver that cause relapsing infections. As a result, ...interruption of P. vivax transmission is difficult. P. vivax transmission occurs in Duffy-positive individuals and have been mainly thought to be absent in Africa. However, increasing studies using molecular tools detected P. vivax among Duffy-negative individuals in various African countries. Studies on the African P. vivax has been severely limited because most of malaria control program focus mainly on falciparum malaria. In addition, there is a scarcity of laboratory infrastructures to overcome the biological obstacles posed by P. vivax. Herein, we established field transmission of Ethiopian P. vivax for routine sporozoite supply followed by liver stage infection in Mali. Furthermore, we evaluated local P. vivax hypnozoites and schizonts susceptibilities to reference antimalarial drugs. The study enabled the assessment of local African P. vivax hypnozoite production dynamics. Our data displayed the ability of the African P. vivax to produce hypnozoite forms ex-vivo at different rates per field isolate. We report that while tafenoquine (1µM) potently inhibited both hypnozoites and schizont forms; atovaquone (0.25µM) and the phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691 (0.5µM) showed no activity against hypnozoites forms. Unlike hypnozoites forms, P. vivax schizont stages were fully susceptible to both atovaquone (0.25µM) and the (PI4K)-specific inhibitor KDU691 (0.5µM). Together, the data revealed the importance of the local platform for further biological investigation and implementation of drug discovery program on the African P. vivax clinical isolates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
28.
COVID-19: Shining the Light on Africa Rosenthal, Philip J; Breman, Joel G; Djimde, Abdoulaye A ...
The American journal of tropical medicine and hygiene,
06/2020, Letnik:
102, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Rosenthal et al discuss COVID-19 in Africa. Africa has faced epidemics throughout its history, from smallpox to recurrent epidemics of malaria, sleeping sickness, and many other lethal diseases. By ...early April, nearly every country in Africa reported COVID-19, with hundreds to thousands of cases reported in the hardest-hit countries, presumably many additional infections that were unidentified, and hundreds of deaths from COVID-19 noted across the continent. Africa has reacted quickly to COVID-19. An emergency meeting of African health ministers to discuss the pandemic was hosted by the African Union Commission on February 22, resulting in the rapid establishment of the Africa Taskforce for Coronavirus Preparedness and Response by the African Union Commission, Africa CDC, and the WHO Regional Office for Africa (AFRO), in partnership with African governments and other stakeholders.
We conducted a randomized single-blinded trial comparing the efficacy and safety of artesunate (AS) + amodiaquine (AQ, 3 days) versus AS (3 days) + sulfadoxine-pyrimethamine (SP, single dose) versus ...AS monotherapy (5 days) in Southern Mali. Uncomplicated malaria cases were followed for 28 days. Molecular markers of drug resistance were determined. After identification of recrudescences by genotyping, both artemisinin-based combination therapies (ACTs) reached nearly 100% efficacy at Day 14 and Day 28 versus 98.3% and 96.5% for AS, respectively (P > 0.05). AS + SP significantly selected DHFR and DHPS mutations associated with sulfadoxine and pyrimethamine resistance (P < 0.001), and AS + AQ equally selected PfCRT and PfMDR1 point mutations associated with chloroquine and AQ resistance (P < 0.001). No significant adverse event attributable to any of the study drugs was found. The ACTs were efficacious and safe, but the selection of markers for resistance to the partner drugs raises concerns over their lifespan in areas of intense malaria transmission.
Background
Novel treatments against for tinea capitis are needed, and the natural aminosterol squalamine is a potential topical antidermatophyte drug candidate.
Objectives
This phase II randomized ...double-blind placebo-controlled clinical trial aimed at testing the efficacy and safety of a three-week squalamine ointment regimen for the treatment of
tinea capitis
.
Patients
Males aged 6–15 years presenting with
tinea capitis
were treated with either topical squalamine ointment or placebo for 3 weeks. The primary endpoint was complete clinical cure. The secondary endpoints were the occurrence of local and/or systemic adverse events, mycological cure, and partial clinical response. Prospective follow-up of clinical adverse events was performed daily.
Results
Five patients were treated with 1 % squalamine ointment and 15 with placebo. No complete cure was observed. No clinical or biological adverse event was recorded. A significantly (
p
= 0.03) better hair-growth score, indicating a partial clinical improvement of the
tinea capitis
lesion, was observed in the patients treated with squalamine compared to those treated with placebo.
Conclusion
This three-week squalamine ointment regimen was well tolerated and showed an encouraging partial clinical activity for the treatment of
tinea capitis
. Further studies are needed to evaluate the efficacy of topical squalamine alone against
tinea corporis
or in combination with a systemic antidermatophyte drug against
tinea capitis
.
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