| 1. |
- Adam, M., et al.
(författare)
-
Antimalarial drug efficacy and resistance in malaria-endemic countries in HANMAT-PIAM_net countries of the Eastern Mediterranean Region 2016-2020: Clinical and genetic studies
- 2023
-
Ingår i: Tropical Medicine & International Health. - 1360-2276. ; 28:10, s. 817-829
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction The World Health Organization recommends regular monitoring of the efficacy of nationally recommended antimalarial drugs. We present the results of studies on the efficacy of recommended antimalarials and molecular markers of artemisinin and partner resistance in Afghanistan, Pakistan, Somalia, Sudan and Yemen.Methods Single-arm prospective studies were conducted to evaluate the efficacy of artesunate-sulfadoxine-pyrimethamine (ASSP) in Afghanistan and Pakistan, artemether-lumefantrine (AL) in all countries, or dihydroartemisinin-piperaquine (DP) in Sudan for the treatment of Plasmodium falciparum. The efficacy of chloroquine (CQ) and AL for the treatment of Plasmodium vivax was evaluated in Afghanistan and Somalia, respectively. Patients were treated and monitored for 28 (CQ, ASSP and AL) or 42 (DP) days. Polymerase chain reaction (PCR)-corrected cure rate and parasite positivity rate at Day 3 were estimated. Mutations in the P. falciparum kelch 13 (Pfk13) gene and amplifications of plasmepsin (Pfpm2) and multidrug resistance-1 (Pfmdr-1) genes were also studied.Results A total of 1680 (249 for ASSP, 1079 for AL and 352 for DP) falciparum cases were successfully assessed. A PCR-adjusted ASSP cure rate of 100% was observed in Afghanistan and Pakistan. For AL, the cure rate was 100% in all but four sites in Sudan, where cure rates ranged from 92.1% to 98.8%. All but one patient were parasite-free at Day 3. For P. vivax, cure rates were 98.2% for CQ and 100% for AL. None of the samples from Afghanistan, Pakistan and Yemen had a Pfk13 mutation known to be associated with artemisinin resistance. In Sudan, the validated Pfk13 R622I mutation accounted for 53.8% (14/26) of the detected non-synonymous Pfk13 mutations, most of which were repeatedly detected in Gadaref. A prevalence of 2.7% and 9.3% of Pfmdr1 amplification was observed in Pakistan and Yemen, respectively.Conclusion High efficacy of ASSP, AL and DP in the treatment of uncomplicated falciparum infection and of CQ and AL in the treatment of P. vivax was observed in the respective countries. The repeated detection of a relatively high rate of Pfk13 R622I mutation in Sudan underscores the need for close monitoring of the efficacy of recommended ACTs, parasite clearance rates and Pfk13 mutations in Sudan and beyond. Registration numbers of the trials: ACTRN12622000944730 and ACTRN12622000873729 for Afghanistan, ACTRN12620000426987 and ACTRN12617001025325 for Pakistan, ACTRN12618001224213 for Somalia, ACTRN12617000276358, ACTRN12622000930785 and ACTRN12618001800213 for Sudan and ACTRN12617000283370 for Yemen.
|
|
| 2. |
|
|
| 3. |
- Ahlberg, Beth Maina, et al.
(författare)
-
'It's only a tradition' : making sense of eradication interventions and the persistence of female 'circumcision' within a Swedish context
- 2004
-
Ingår i: Critical Social Policy. - London : Sage Publications. - 0261-0183 .- 1461-703X. ; 24:1, s. 50-78
-
Tidskriftsartikel (refereegranskat)abstract
- This paper questions why female circumcision (FC) persists despite eradication interventions and the migration of people to non-practising countries and discusses the reasoning of Somali immigrants on female circumcision. It is based on interviews with diverse groups and individuals in the Somali community, mostly refugees in Sweden. Paradoxes implying denial and avoidance emerged. Female circumcision was described, as just 'a tradition' that has little to do with Islam. The fear of bringing up an uncircumcised daughter in the liberal sexual morality of Sweden was mentioned as a dilemma. Circumcised women said the health care they received during pregnancy and childbirth was poor while the law failed to take account of the experiences of the Somali people. We conclude that rather than eradication, interventions seem to have silenced and stigmatized the practice due to their failure to take account of its meanings, organization and contexts, including the diasporic dynamics within which immigrants negotiate identities.
|
|
| 4. |
- Baird, J. K., et al.
(författare)
-
Survey and Analysis of Chemoprophylaxis Policies for Domestic Travel in Malaria-Endemic Countries
- 2022
-
Ingår i: Tropical Medicine and Infectious Disease. - : MDPI AG. - 2414-6366. ; 7:7
-
Tidskriftsartikel (refereegranskat)abstract
- The prevention of malaria in travelers with the use of antimalarials often occurs in connection with international travel to areas of significant risk of infection. Although these travelers sometimes cause outbreaks in their malaria-free home countries, the cardinal objective of prescribed chemoprophylaxis is to protect the traveler from patent malaria during travel. Here we consider the chemoprophylaxis of domestic travelers from malaria-free but -receptive areas within malaria-endemic countries. The main objective in this setting is the protection of those areas from reintroduced malaria transmission. In order to better understand policy and practices in this regard, we surveyed malaria prevention and treatment guidelines of 36 malaria-endemic countries and 2 that have recently eliminated malaria (Sri Lanka, China) for recommendations regarding malaria chemoprophylaxis for domestic travel. Among them, just 8 provided specific and positive recommendations, 1 recommended without specific guidance, and 4 advised against the practice. Most nations (25/38; 66%) did not mention chemoprophylaxis for domestic travel, though many of those did offer guidance for international travel. The few positive recommendations for domestic travel were dominated by the suppressive prophylaxis options of daily doxycycline or atovaquone-proguanil or weekly mefloquine. The incomplete protection afforded by these strategies, along with impractical dosing in connection with the typically brief domestic travel, may in part explain the broad lack of policies and practices across malaria-endemic nations regarding chemoprophylaxis.
|
|
| 5. |
- Bakari, Catherine, et al.
(författare)
-
Trends of Plasmodium falciparum molecular markers associated with resistance to artemisinins and reduced susceptibility to lumefantrine in Mainland Tanzania from 2016 to 2021
- 2024
-
Ingår i: MALARIA JOURNAL. - 1475-2875. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background Therapeutic efficacy studies (TESs) and detection of molecular markers of drug resistance are recommended by the World Health Organization (WHO) to monitor the efficacy of artemisinin-based combination therapy (ACT). This study assessed the trends of molecular markers of artemisinin resistance and/or reduced susceptibility to lumefantrine using samples collected in TES conducted in Mainland Tanzania from 2016 to 2021. Methods A total of 2,015 samples were collected during TES of artemether-lumefantrine at eight sentinel sites (in Kigoma, Mbeya, Morogoro, Mtwara, Mwanza, Pwani, Tabora, and Tanga regions) between 2016 and 2021. Photo-induced electron transfer polymerase chain reaction (PET-PCR) was used to confirm presence of malaria parasites before capillary sequencing, which targeted two genes: Plasmodium falciparum kelch 13 propeller domain (k13) and P. falciparum multidrug resistance 1 (pfmdr1). Results Sequencing success was >= 87.8%, and 1,724/1,769 (97.5%) k13 wild-type samples were detected. Thirty-seven (2.1%) samples had synonymous mutations and only eight (0.4%) had non-synonymous mutations in the k13 gene; seven of these were not validated by the WHO as molecular markers of resistance. One sample from Morogoro in 2020 had a k13 R622I mutation, which is a validated marker of artemisinin partial resistance. For pfmdr1, all except two samples carried N86 (wild-type), while mutations at Y184F increased from 33.9% in 2016 to about 60.5% in 2021, and only four samples (0.2%) had D1246Y mutations. pfmdr1 haplotypes were reported in 1,711 samples, with 985 (57.6%) NYD, 720 (42.1%) NFD, and six (0.4%) carrying minor haplotypes (three with NYY, 0.2%; YFD in two, 0.1%; and NFY in one sample, 0.1%). Between 2016 and 2021, NYD decreased from 66.1% to 45.2%, while NFD increased from 38.5% to 54.7%. Conclusion This is the first report of the R622I (k13 validated mutation) in Tanzania. N86 and D1246 were nearly fixed, while increases in Y184F mutations and NFD haplotype were observed between 2016 and 2021. Despite the reports of artemisinin partial resistance in Rwanda and Uganda, this study did not report any other validated mutations in these study sites in Tanzania apart from R622I suggesting that intensified surveillance is urgently needed to monitor trends of drug resistance markers and their impact on the performance of ACT.
|
|
| 6. |
- Brabin, Bernard J., et al.
(författare)
-
Monitoring and evaluation of malaria in pregnancy - developing a rational basis for control
- 2008
-
Ingår i: Malaria Journal. - 1475-2875. ; 7:Suppl. 1
-
Forskningsöversikt (refereegranskat)abstract
- Monitoring and evaluation of malaria control in pregnancy is essential for assessing the efficacy and effectiveness of health interventions aimed at reducing the major burden of this disease on women living in endemic areas. Yet there is no currently integrated strategic approach on how this should be achieved. Malaria control in pregnancy is formulated in relation to epidemiological patterns of exposure. Current emphasis is on intermittent preventive treatment (IPTp) during pregnancy with sulphadoxine-pyrimethamine in higher transmission areas, combined with insecticide treated bed nets (ITNs) and case management. Emphasis in lower transmission areas is primarily on case management. This paper discusses a rational basis for monitoring and evaluation based on: assessments of therapeutic and prophylactic drug efficacy; proportional reductions in parasite prevalence; seasonal effects; rapid assessment methodologies; birthweight and/or anaemia nomograms; case-coverage methods; maternal mortality indices; operational and programmatic indicators; and safety and pharmacovigilance of antimalarials in pregnancy. These approaches should be incorporated more effectively within National Programmes in order to facilitate surveillance and improve identification of high-risk women. Systems for utilizing routinely collected data should be strengthened, with greater attention to safety and pharmacovigilance with the advent of artemisinin combination therapies, and prospects of inadvertent exposures to artemisinins in the first trimester. Integrating monitoring activities within malaria control, reproductive health and adolescent-friendly services will be critical for implementation. Large-scale operational research is required to further evaluate the validity of currently proposed indicators, and in order to clarify the breadth and scale of implementation to be deployed.
|
|
| 7. |
- Dalmar, Abdirisak Ahmed, et al.
(författare)
-
Rebuilding research capacity in fragile states : the case of a Somali-Swedish global health initiative
- 2017
-
Ingår i: Global Health Action. - Abingdon : Informa UK Limited. - 1654-9716 .- 1654-9880. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- This paper presents an initiative to revive the previous Somali-Swedish Research Cooperation, which started in 1981 and was cut short by the civil war in Somalia. A programme focusing on research capacity building in the health sector is currently underway through the work of an alliance of three partner groups: six new Somali universities, five Swedish universities, and Somali diaspora professionals. Somali ownership is key to the sustainability of the programme, as is close collaboration with Somali health ministries. The programme aims to develop a model for working collaboratively across regions and cultural barriers within fragile states, with the goal of creating hope and energy. It is based on the conviction that health research has a key role in rebuilding national health services and trusted institutions.
|
|
| 8. |
- Dorkenoo, Ameyo Monique, et al.
(författare)
-
Efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine and prevalence of molecular markers of anti-malarial drug resistance in children in Togo in 2021
- 2024
-
Ingår i: MALARIA JOURNAL. - 1475-2875. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are the currently recommended first- and second-line therapies for uncomplicated Plasmodium falciparum infections in Togo. This study assessed the efficacy of these combinations, the proportion of Day3-positive patients (D3 +), the proportion of molecular markers associated with P. falciparum resistance to anti-malarial drugs, and the variable performance of HRP2-based malaria rapid diagnostic tests (RDTs).Methods A single arm prospective study evaluating the efficacy of AL and DP was conducted at two sites (Kouve and Anie) from September 2021 to January 2022. Eligible children were enrolled, randomly assigned to treatment at each site and followed up for 42 days after treatment initiation. The primary endpoint was polymerase chain reaction (PCR) adjusted adequate clinical and parasitological response (ACPR). At day 0, samples were analysed for mutations in the Pfkelch13, Pfcrt, Pfmdr-1, dhfr, dhps, and deletions in the hrp2/hrp3 genes.Results A total of 179 and 178 children were included in the AL and DP groups, respectively. After PCR correction, cure rates of patients treated with AL were 97.5% (91.4-99.7) at day 28 in Kouve and 98.6% (92.4-100) in Anie, whereas 96.4% (CI 95%: 89.1-98.8) and 97.3% (CI 95%: 89.5-99.3) were observed at day 42 in Kouve and Anie, respectively. The cure rates of patients treated with DP at day 42 were 98.9% (CI 95%: 92.1-99.8) in Kouve and 100% in Anie. The proportion of patients with parasites on day 3 (D3 +) was 8.5% in AL and 2.6% in DP groups in Anie and 4.3% in AL and 2.1% DP groups in Kouve. Of the 357 day 0 samples, 99.2% carried the Pfkelch13 wild-type allele. Two isolates carried nonsynonymous mutations not known to be associated with artemisinin partial resistance (ART-R) (A578S and A557S). Most samples carried the Pfcrt wild-type allele (97.2%). The most common Pfmdr-1 allele was the single mutant 184F (75.6%). Among dhfr/dhps mutations, the quintuple mutant haplotype N51I/C59R/S108N + 437G/540E, which is responsible for SP treatment failure in adults and children, was not detected. Single deletions in hrp2 and hrp3 genes were detected in 1/357 (0.3%) and 1/357 (0.3%), respectively. Dual hrp2/hrp3 deletions, which could affect the performances of HRP2-based RDTs, were not observed.Conclusion The results of this study confirm that the AL and DP treatments are highly effective. The absence of the validated Pfkelch13 mutants in the study areas suggests the absence of ART -R, although a significant proportion of D3 + cases were found. The absence of dhfr/dhps quintuple or sextuple mutants (quintuple + 581G) supports the continued use of SP for IPTp during pregnancy and in combination with amodiaquine for seasonal malaria chemoprevention. Trial registration: ACTRN12623000344695.Conclusion The results of this study confirm that the AL and DP treatments are highly effective. The absence of the validated Pfkelch13 mutants in the study areas suggests the absence of ART -R, although a significant proportion of D3 + cases were found. The absence of dhfr/dhps quintuple or sextuple mutants (quintuple + 581G) supports the continued use of SP for IPTp during pregnancy and in combination with amodiaquine for seasonal malaria chemoprevention. Trial registration: ACTRN12623000344695.
|
|
| 9. |
- Ishengoma, Deus S., et al.
(författare)
-
Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated malaria and prevalence of Pfk13 and Pfmdr1 polymorphisms after a decade of using artemisinin-based combination therapy in mainland Tanzania
- 2019
-
Ingår i: Malaria Journal. - : BMC. - 1475-2875. ; 18
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The World Health Organization recommends regular therapeutic efficacy studies (TES) to monitor the performance of first and second-line anti-malarials. In 2016, efficacy and safety of artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria were assessed through a TES conducted between April and October 2016 at four sentinel sites of Kibaha, Mkuzi, Mlimba, and Ujiji in Tanzania. The study also assessed molecular markers of artemisinin and lumefantrine (partner drug) resistance.Methods: Eligible patients were enrolled at the four sites, treated with standard doses of AL, and monitored for 28 days with clinical and laboratory assessments. The main outcomes were PCR corrected cure rates, day 3 positivity rates, safety of AL, and prevalence of single nucleotide polymorphisms in Plasmodium falciparum kelch 13 (Pfk13) (codon positions: 440-600) and P. falciparum multi-drug resistance 1 (Pfmdr1) genes (codons: N86Y, Y184F and D1246Y), markers of artemisinin and lumefantrine resistance, respectively.Results: Of 344 patients enrolled, three withdrew, six were lost to follow-up; and results were analysed for 335 (97.4%) patients. Two patients had treatment failure (one early treatment failure and one recrudescent infection) after PCR correction, yielding an adequate clinical and parasitological response of > 98%. Day 3 positivity rates ranged from 0 to 5.7%. Common adverse events included cough, abdominal pain, vomiting, and diarrhoea. Two patients had serious adverse events; one died after the first dose of AL and another required hospitalization after the second dose of AL (on day 0) but recovered completely. Of 344 samples collected at enrolment (day 0), 92.7% and 100% were successfully sequenced for Pfk13 and Pfmdr1 genes, respectively. Six (1.9%) had non-synonymous mutations in Pfk13, none of which had been previously associated with artemisinin resistance. For Pfmdr1, the NFD haplotype (codons N86, 184F and D1246) was detected in 134 (39.0%) samples; ranging from 33.0% in Mlimba to 45.5% at Mkuzi. The difference among the four sites was not significant (p = 0.578). All samples had a single copy of the Pfmdr1 gene.Conclusion: The study indicated high efficacy of AL and the safety profile was consistent with previous reports. There were no known artemisinin-resistance Pfk13 mutations, but there was a high prevalence of a Pfmdr1 haplotype associated with reduced sensitivity to lumefantrine (but no reduced efficacy was observed in the subjects). Continued TES and monitoring of markers of resistance to artemisinin and partner drugs is critical for early detection of resistant parasites and to inform evidence-based malaria treatment policies.
|
|
| 10. |
- Ishengoma, Deus S., et al.
(författare)
-
Microsatellites reveal high polymorphism and high potential for use in anti-malarial efficacy studies in areas with different transmission intensities in mainland Tanzania
- 2024
-
Ingår i: MALARIA JOURNAL. - : Springer Nature. - 1475-2875. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background Tanzania is currently implementing therapeutic efficacy studies (TES) in areas of varying malaria transmission intensities as per the World Health Organization (WHO) recommendations. In TES, distinguishing reinfection from recrudescence is critical for the determination of anti-malarial efficacy. Recently, the WHO recommended genotyping polymorphic coding genes, merozoite surface proteins 1 and 2 (msp1 and msp2), and replacing the glutamate-rich protein (glurp) gene with one of the highly polymorphic microsatellites in Plasmodium falciparum to adjust the efficacy of antimalarials in TES. This study assessed the polymorphisms of six neutral microsatellite markers and their potential use in TES, which is routinely performed in Tanzania. Methods Plasmodium falciparum samples were obtained from four TES sentinel sites, Kibaha (Pwani), Mkuzi (Tanga), Mlimba (Morogoro) and Ujiji (Kigoma), between April and September 2016. Parasite genomic DNA was extracted from dried blood spots on filter papers using commercial kits. Genotyping was done using six microsatellites (Poly-alpha, PfPK2, TA1, C3M69, C2M34 and M2490) by capillary method, and the data were analysed to determine the extent of their polymorphisms and genetic diversity at the four sites. Results Overall, 83 (88.3%) of the 94 samples were successfully genotyped (with positive results for >= 50.0% of the markers), and > 50.0% of the samples (range = 47.6-59.1%) were polyclonal, with a mean multiplicity of infection (MOI) ranging from 1.68 to 1.88 among the four sites. There was high genetic diversity but limited variability among the four sites based on mean allelic richness (R-S = 7.48, range = 7.27-8.03, for an adjusted minimum sample size of 18 per site) and mean expected heterozygosity (H-e = 0.83, range = 0.80-0.85). Cluster analysis of haplotypes using STRUCTURE, principal component analysis, and pairwise genetic differentiation (F-ST) did not reveal population structure or clustering of parasites according to geographic origin. Of the six markers, Poly-alpha was the most polymorphic, followed by C2M34, TA1 and C3M69, while M2490 was the least polymorphic. Conclusion Microsatellite genotyping revealed high polyclonality and genetic diversity but no significant population structure. Poly-alpha, C2M34, TA1 and C3M69 were the most polymorphic markers, and Poly-alpha alone or with any of the other three markers could be adopted for use in TES in Tanzania.
|
|
| 11. |
- Issa, M. S., et al.
(författare)
-
Therapeutic efficacy of artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Chad: clinical and genetic surveillance
- 2023
-
Ingår i: Malaria Journal. ; 22:1
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundArtesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) are the currently recommended first-and second-line therapies for uncomplicated Plasmodium falciparum infections in Chad. This study assessed the efficacy of these artemisinin-based combinations, proportion of day 3 positive patients, proportions of molecular markers associated with P. falciparum resistance to anti-malarial drugs and variable performance of HRP2-based malaria rapid diagnostic tests (RDTs).MethodsA single-arm prospective study assessing the efficacy of AS-AQ and AL at three sites (Doba, Kelo and Koyom) was conducted between November 2020 to January 2021. Febrile children aged 6 to 59 months with confirmed uncomplicated P. falciparum infection were enrolled sequentially first to AS-AQ and then AL at each site and followed up for 28 days. The primary endpoint was PCR-adjusted adequate clinical and parasitological response (ACPR). Samples collected on day 0 were analysed for mutations in pfkelch13, pfcrt, pfmdr-1, pfdhfr, pfdhps genes and deletions in pfhrp2/pfhrp3 genes.ResultsBy the end of 28-day follow-up, per-protocol PCR corrected ACPR of 97.8% (CI 95% 88.2-100) in Kelo and 100% in Doba and Kayoma were observed among AL treated patients. For ASAQ, 100% ACPR was found in all sites. All, but one patient, did not have parasites detected on day 3. Out of the 215 day 0 samples, 96.7% showed pfkelch13 wild type allele. Seven isolates carried nonsynonymous mutations not known to be associated artemisinin partial resistance (ART-R). Most of samples had a pfcrt wild type allele (79% to 89%). The most prevalent pfmdr-1 allele detected was the single mutant 184F (51.2%). For pfdhfr and pfdhps mutations, the quintuple mutant allele N51I/C59R/S108N + G437A/540E responsible for SP treatment failures in adults and children was not detected. Single deletion in the pfhrp2 and pfhrp3 gene were detected in 10/215 (4.7%) and 2/215 (0.9%), respectively. Dual pfhrp2/pfhrp3 deletions, potentially threatening the efficacy of HRP2-based RDTs, were observed in 5/215 (2.3%) isolates.ConclusionThe results of this study confirm that AS-AQ and AL treatments are highly efficacious in study areas in Chad. The absence of known pfkelch13 mutations in the study sites and the high parasite clearance rate at day 3 suggest the absence of ART-R. The absence of pfdhfr/pfdhps quintuple or sextuple (quintuple + 581G) mutant supports the continued use of SP for IPTp during pregnancy. The presence of parasites with dual pfhrp2/pfhrp3 deletions, potentially threatening the efficacy of HRP2-based RDTs, warrants the continued surveillance.Trial registration ACTRN12622001476729ConclusionThe results of this study confirm that AS-AQ and AL treatments are highly efficacious in study areas in Chad. The absence of known pfkelch13 mutations in the study sites and the high parasite clearance rate at day 3 suggest the absence of ART-R. The absence of pfdhfr/pfdhps quintuple or sextuple (quintuple + 581G) mutant supports the continued use of SP for IPTp during pregnancy. The presence of parasites with dual pfhrp2/pfhrp3 deletions, potentially threatening the efficacy of HRP2-based RDTs, warrants the continued surveillance.Trial registration ACTRN12622001476729
|
|
| 12. |
- Koko, V. S., et al.
(författare)
-
Artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Liberia: in vivo efficacy and frequency of molecular markers
- 2022
-
Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 21:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Artesunate-amodiaquine (ASAQ) and Artemether-lumefantrine (AL) are the recommended treatment for uncomplicated Plasmodium falciparum malaria in Liberia. Intermittent preventive treatment with sulfadoxine/pyrimethamine is also recommended for pregnant women. The therapeutic efficacy of Artesunate-amodiaquine and Artemether-lumefantrine, and the frequency of molecular markers associated with anti-malarial drug resistance were investigated. Methods: The therapeutic efficacy of ASAQ and AL was evaluated using the standard World Health Organization protocol (WHO. Methods for Surveillance of Antimalarial Drug Efficacy. Geneva: World Health Organization; 2009. https://www.who.int/malaria/publications/atoz/9789241597531/en/). Eligible children were recruited and monitored clinically and parasitologically for 28 days. Polymorphisms in the Pfkelch 13, chloroquine resistance transporter (Pfcrt), multidrug resistance 1 (Pfmdr-1), dihydrofolate reductase (Pfdhfr), and dihydropteroate synthase (Pfdhps) genes and copy number variations in the plasmepsin-2 (Pfpm2) gene were assessed in pretreatment samples. Results: Of the 359 children enrolled, 180 were treated with ASAQ (89 in Saclepea and 91 in Bensonville) and 179 with AL (90 in Sinje and 89 in Kakata). Of the recruited children, 332 (92.5%) reached study endpoints. PCR-corrected per-protocol analysis showed ACPR of 90.2% (95% CI: 78.6-96.7%) in Bensonville and 92.7% (95% CI: 83.4.8-96.5%) in Saclepea for ASAQ, while ACPR of 100% was observed in Kakata and Sinje for AL. In both treatment groups, only two patients had parasites on day 3. No artemisinin resistance associated Pfkelch13 mutations or multiple copies of Pfpm2 were found. Most samples tested had the Pfcrt 76 T mutation (80/91, 87.9%), while the Pfmdr-1 86Y (40/91, 44%) and 184F (47/91, 51.6%) mutations were less frequent. The Pfdhfr triple mutant (51I/59R/108 N) was the predominant allele (49.2%). For the Pfdhps gene, it was the 540E mutant (16.0%), and the 436A mutant (14.3%). The quintuple allele (51I/59R/108 N-437G/540E) was detected in only one isolate (1/357). Conclusion: This study reports a decline in the efficacy of ASAQ treatment, while AL remained highly effective, supporting the recent decision by NMCP to replace ASAQ with AL as first-line treatment for uncomplicated falciparum malaria. No association between the presence of the mutations in Pfcrt and Pfmdr-1 and the risk of parasite recrudescence in patients treated with ASAQ was observed. Parasites with signatures known to be associated with artemisinin and piperaquine resistance were not detected. The very low frequency of the quintuple Pfdhfr/Pfdhps mutant haplotype supports the continued use of SP for IPTp. Monitoring of efficacy and resistance markers of routinely used anti-malarials is necessary to inform malaria treatment policy.
|
|
| 13. |
- Mihreteab, Selam, et al.
(författare)
-
Increasing Prevalence of Artemisinin-Resistant HRP2-Negative Malaria in Eritrea
- 2023
-
Ingår i: NEW ENGLAND JOURNAL OF MEDICINE. - 0028-4793 .- 1533-4406. ; 389:13, s. 1191-1202
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundAlthough the clinical efficacy of antimalarial artemisinin-based combination therapies in Africa remains high, the recent emergence of partial resistance to artemisinin in Plasmodium falciparum on the continent is troubling, given the lack of alternative treatments.MethodsIn this study, we used data from drug-efficacy studies conducted between 2016 and 2019 that evaluated 3-day courses of artemisinin-based combination therapy (artesunate-amodiaquine or artemether-lumefantrine) for uncomplicated malaria in Eritrea to estimate the percentage of patients with day-3 positivity (i.e., persistent P. falciparum parasitemia 3 days after the initiation of therapy). We also assayed parasites for mutations in Pfkelch13 as predictive markers of partial resistance to artemisinin and screened for deletions in hrp2 and hrp3 that result in variable performance of histidine rich protein 2 (HRP2)-based rapid diagnostic tests for malaria.ResultsWe noted an increase in the percentage of patients with day-3 positivity from 0.4% (1 of 273) in 2016 to 1.9% (4 of 209) in 2017 and 4.2% (15 of 359) in 2019. An increase was also noted in the prevalence of the Pfkelch13 R622I mutation, which was detected in 109 of 818 isolates before treatment, from 8.6% (24 of 278) in 2016 to 21.0% (69 of 329) in 2019. The odds of day-3 positivity increased by a factor of 6.2 (95% confidence interval, 2.5 to 15.5) among the patients with Pfkelch13 622I variant parasites. Partial resistance to artemisinin, as defined by the World Health Organization, was observed in Eritrea. More than 5% of the patients younger than 15 years of age with day-3 positivity also had parasites that carried Pfkelch13 R622I. In vitro, the R622I mutation conferred a low level of resistance to artemisinin when edited into NF54 and Dd2 parasite lines. Deletions in both hrp2 and hrp3 were identified in 16.9% of the parasites that carried the Pfkelch13 R622I mutation, which made them potentially undetectable by HRP2-based rapid diagnostic tests.ConclusionsThe emergence and spread of P. falciparum lineages with both Pfkelch13-mediated partial resistance to artemisinin and deletions in hrp2 and hrp3 in Eritrea threaten to compromise regional malaria control and elimination campaigns. This study shows the emergence and spread of artemisinin resistance, along with the loss of hrp2 required for malaria rapid diagnostic tests, in P. falciparum in Eritrea.
|
|
| 14. |
- Moser, K. A., et al.
(författare)
-
Describing the current status of Plasmodium falciparum population structure and drug resistance within mainland Tanzania using molecular inversion probes
- 2021
-
Ingår i: Molecular Ecology. - : Wiley. - 0962-1083 .- 1365-294X. ; 30:1, s. 100-113
-
Tidskriftsartikel (refereegranskat)abstract
- High-throughput Plasmodium genomic data is increasingly useful in assessing prevalence of clinically important mutations and malaria transmission patterns. Understanding parasite diversity is important for identification of specific human or parasite populations that can be targeted by control programmes, and to monitor the spread of mutations associated with drug resistance. An up-to-date understanding of regional parasite population dynamics is also critical to monitor the impact of control efforts. However, this data is largely absent from high-burden nations in Africa, and to date, no such analysis has been conducted for malaria parasites in Tanzania countrywide. To this end, over 1,000 P. falciparum clinical isolates were collected in 2017 from 13 sites in seven administrative regions across Tanzania, and parasites were genotyped at 1,800 variable positions genome-wide using molecular inversion probes. Population structure was detectable among Tanzanian P. falciparum parasites, approximately separating parasites from the northern and southern districts and identifying genetically admixed populations in the north. Isolates from nearby districts were more likely to be genetically related compared to parasites sampled from more distant districts. Known drug resistance mutations were seen at increased frequency in northern districts (including two infections carrying pfk13-R561H), and additional variants with undetermined significance for antimalarial resistance also varied by geography. Malaria Indicator Survey (2017) data corresponded with genetic findings, including average region-level complexity-of-infection and malaria prevalence estimates. The parasite populations identified here provide important information on extant spatial patterns of genetic diversity of Tanzanian parasites, to which future surveys of genetic relatedness can be compared. © 2020 John Wiley & Sons Ltd
|
|
| 15. |
- Ngasala, Billy E., et al.
(författare)
-
Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2019
- 2024
-
Ingår i: MALARIA JOURNAL. - 1475-2875. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background Artemisinin-based combination therapy (ACT) has been a major contributor to the substantial reductions in global malaria morbidity and mortality over the last decade. In Tanzania, artemether-lumefantrine (AL) was introduced as the first-line treatment for uncomplicated Plasmodium falciparum malaria in 2006. The World Health Organization (WHO) recommends regular assessment and monitoring of the efficacy of the first-line treatment, specifically considering that artemisinin resistance has been confirmed in the Greater Mekong sub-region. This study's main aim was to assess the efficacy and safety of AL for treating uncomplicated P. falciparum malaria in Tanzania.Methods This was a single-arm prospective antimalarial drug efficacy trial conducted in four of the eight National Malaria Control Programme (NMCP) sentinel sites in 2019. The trial was carried out in outpatient health facilities in Karume-Mwanza region, Ipinda-Mbeya region, Simbo-Tabora region, and Nagaga-Mtwara region. Children aged six months to 10 years with microscopy confirmed uncomplicated P. falciparum malaria who met the inclusion criteria were recruited based on the WHO protocol. The children received AL (a 6-dose regimen of AL twice daily for three days). Clinical and parasitological parameters were monitored during follow-up over 28 days to evaluate drug efficacy.Results A total of 628 children were screened for uncomplicated malaria, and 349 (55.6%) were enrolled between May and September 2019. Of the enrolled children, 343 (98.3%) completed the 28-day follow-up or attained the treatment outcomes. There were no early treatment failures; recurrent infections during follow-up were common at two sites (Karume 29.5%; Simbo 18.2%). PCR-corrected adequate clinical and parasitological response (ACPR) by survival analysis to AL on day 28 of follow-up varied from 97.7% at Karume to 100% at Ipinda and Nagaga sites. The commonly reported adverse events were cough, skin pallor, and abdominal pain. The drug was well tolerated, and no serious adverse event was reported.Conclusion This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria in Tanzania in 2019. The high recurrent infections were mainly due to new infections, highlighting the potential role of introducing alternative artemisinin-based combinations that offer improved post-treatment prophylaxis, such as artesunate-amodiaquine (ASAQ).
|
|
| 16. |
- Ngasala, Billy, et al.
(författare)
-
Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2018
- 2024
-
Ingår i: MALARIA JOURNAL. - 1475-2875. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background The use of artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated falciparum malaria. Artemether-lumefantrine (AL) is the most widely adopted first-line ACT for uncomplicated malaria in sub-Saharan Africa (SSA), including mainland Tanzania, where it was introduced in December 2006. The WHO recommends regular assessment to monitor the efficacy of the first-line treatment specifically considering that artemisinin partial resistance was reported in Greater Mekong sub-region and has been confirmed in East Africa (Rwanda and Uganda). The main aim of this study was to assess the efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in mainland Tanzania.Methods A single-arm prospective anti-malarial drug efficacy trial was conducted in Kibaha, Mlimba, Mkuzi, and Ujiji (in Pwani, Morogoro, Tanga, and Kigoma regions, respectively) in 2018. The sample size of 88 patients per site was determined based on WHO 2009 standard protocol. Participants were febrile patients (documented axillary temperature >= 37.5 degrees C and/or history of fever during the past 24 h) aged 6 months to 10 years. Patients received a 6-dose AL regimen by weight twice a day for 3 days. Clinical and parasitological parameters were monitored during 28 days of follow-up to evaluate the drug efficacy and safety.Results A total of 653 children were screened for uncomplicated malaria and 349 (53.7%) were enrolled between April and August 2018. Of the enrolled children, 345 (98.9%) completed the 28 days of follow-up or attained the treatment outcomes. There were no early treatment failures, but recurrent infections were higher in Mkuzi (35.2%) and Ujiji (23%). By Kaplan-Meier analysis of polymerase chain reaction (PCR) uncorrected adequate clinical and parasitological response (ACPR) ranged from 63.4% in Mkuzi to 85.9% in Mlimba, while PCR-corrected ACPR on day 28 varied from 97.6% in Ujiji to 100% in Mlimba. The drug was well tolerated; the commonly reported adverse events were cough, runny nose, and abdominal pain. No serious adverse event was reported.Conclusion This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria. The high number of recurrent infections were mainly due to new infections, indicating the necessity of utilizing alternative artemisinin-based combinations, such as artesunate amodiaquine, which provide a significantly longer post-treatment prophylactic effect.
|
|
| 17. |
- Rivas, M. R., et al.
(författare)
-
Therapeutic efficacy of artesunate-amodiaquine and artemether-lumefantrine and polymorphism in Plasmodium falciparum kelch13-propeller gene in Equatorial Guinea
- 2021
-
Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 20:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are the currently recommended first- and second-line therapies for uncomplicated Plasmodium falciparum infections in Equatorial Guinea. This study was designed to evaluate the efficacy of these artemisinin-based combinations and detect mutations in P. falciparum kelch13-propeller domain gene (Pfkelch13). Methods: A single-arm prospective study evaluating the efficacy of ASAQ and AL at three sites: Malabo, Bata and Ebebiyin was conducted between August 2017 and July 2018. Febrile children aged six months to 10 years with confirmed uncomplicated P. falciparum infection and other inclusion criteria were sequentially enrolled first in ASAQ and then in AL at each site, and followed up for 28 days. Clinical and parasitological parameters were assessed. The primary endpoint was PCR-adjusted adequate clinical and parasitological response (ACPR). Samples on day-0 were analysed for mutations in Pfkelch13 gene. Results: A total 264 and 226 patients were enrolled in the ASAQ and AL treatment groups, respectively. Based on per-protocol analysis, PCR-adjusted cure rates of 98.6% to 100% and 92.4% to 100% were observed in patients treated with ASAQ and AL, respectively. All study children in both treatment groups were free of parasitaemia by day-3. Of the 476 samples with interpretable results, only three samples carried non-synonymous Pfkelch13 mutations (E433D and A578S), and none of them is the known markers associated with artemisinin resistance. Conclusion: The study confirmed high efficacy of ASAQ and AL for the treatment of uncomplicated falciparum infections as well as the absence of delayed parasite clearance and Pfkelch13 mutations associated with artemisinin resistance. Continued monitoring of the efficacy of these artemisinin-based combinations, at least every two years, along with molecular markers associated with artemisinin and partner drug resistance is imperative to inform national malaria treatment policy and detect resistant parasites early. Trial registration ACTRN12617000456358, Registered 28 March 2017;
|
|
| 18. |
- Stokes, B. H., et al.
(författare)
-
Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness
- 2021
-
Ingår i: eLife. - 2050-084X. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failures across Southeast Asia. In Africa, K13-propeller genotyping confirms the emergence of the R561 H mutation in Rwanda and highlights the continuing dominance of wild-type K13 elsewhere. Using gene editing, we show that R561 H, along with C580Y and M5791, confer elevated in vitro ART resistance in some African strains, contrasting with minimal changes in ART susceptibility in others. C580Y and M5791 cause substantial fitness costs, which may slow their dissemination in high-transmission settings, in contrast with R561 H that in African 3D7 parasites is fitness neutral. In Cambodia, K13 genotyping highlights the increasing spatio-temporal dominance of C580Y. Editing multiple K13 mutations into a panel of Southeast Asian strains reveals that only the R561 H variant yields ART resistance comparable to C580Y. In Asian Dd2 parasites C580Y shows no fitness cost, in contrast with most other K13 mutations tested, including R561H. Editing of point mutations in ferredoxin or mdr2, earlier associated with resistance, has no impact on ART susceptibility or parasite fitness. These data underline the complex interplay between K13 mutations, parasite survival, growth and genetic background in contributing to the spread of ART resistance.
|
|
| 19. |
- Uwimana, A., et al.
(författare)
-
Emergence and clonal expansion of in vitro artemisinin-resistantPlasmodium falciparum kelch13R561H mutant parasites in Rwanda
- 2020
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 26, s. 1602-1608
-
Tidskriftsartikel (refereegranskat)abstract
- Artemisinin resistance (delayedP. falciparumclearance following artemisinin-based combination therapy), is widespread across Southeast Asia but to date has not been reported in Africa(1-4). Here we genotyped theP. falciparum K13(Pfkelch13) propeller domain, mutations in which can mediate artemisinin resistance(5,6), in pretreatment samples collected from recent dihydroarteminisin-piperaquine and artemether-lumefantrine efficacy trials in Rwanda(7). While cure rates were >95% in both treatment arms, thePfkelch13R561H mutation was identified in 19 of 257 (7.4%) patients at Masaka. Phylogenetic analysis revealed the expansion of an indigenous R561H lineage. Gene editing confirmed that this mutation can drive artemisinin resistance in vitro. This study provides evidence for the de novo emergence ofPfkelch13-mediated artemisinin resistance in Rwanda, potentially compromising the continued success of antimalarial chemotherapy in Africa. Identification in Rwanda of mutations inPlasmodium falciparumcapable of conferring in vitro resistance to artemisinin, an essential medicine for the treatment of malaria, underscore the crucial need for surveillance in Africa to safeguard efficacy of life-saving therapies.
|
|
| 20. |
- Warsame, Marian, et al.
(författare)
-
Current guidelines for malaria treatment in Somalia : evidence-based recommendations
- 2021
-
Ingår i: Somali Health Action Journal. - Umeå : Umeå University. - 2004-1985. ; 1:1
-
Tidskriftsartikel (refereegranskat)abstract
- Case management – rapid diagnosis and prompt administration of artemisinin-based combination therapy (ACT) – is a fundamental pillar of recommended malaria interventions in Somalia. Unfortunately, the emergence and spread of drug resistant falciparum parasites continues to pose a considerable threat to effective case management.With technical and financial support from WHO, the efficacy of recommended ACTs has been regularly monitored in sentinel sites since 2003. These studies provided evidence that supported the adoption of artesunate-sulfadoxine/pyrimethamine as first-line treatment in 2005 and artemether-lumefantrine as second-line treatment in 2011. Efficacy studies conducted between 2011 and 2015 showed high artesunate-sulfadoxine/pyrimethamine treatment failure rates of 12.3% - 22.2%, above the threshold (10%) for a change of treatment policy as recommended by WHO. This was also associated with high prevalence of quadruple and quintuple mutations in the dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes, which are associated with sulfadoxine/pyrimethamine resistance.Based on these findings, national malaria treatment guidelines were updated in 2016, with artesunate-sulfadoxine/pyrimethamine replaced by artemether-lumefantrine as first-line treatment and dihydroartemisinin-piperaquine recommended as second-line treatment. Subsequent efficacy studies in 2016 and 2017 confirmed that both the current first- and second-line treatments remain highly efficacious (cure rate above 97%). Technical and financial support from WHO has been instrumental in generating evidence that informs malaria treatment policy and should therefore continue to ensure that effective treatments are available to malaria patients in the country.
|
|
| 21. |
- Warsame, Marian, et al.
(författare)
-
High therapeutic efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Somalia
- 2019
-
Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 18
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA/PPQ) are the recommended first- and second-line treatments, respectively, for uncomplicated falciparum malaria in Somalia. The studies reported here were conducted to assess the efficacy of these artemisinin-based combinations and the mutations in Plasmodium falciparum K13-propeller (Pfk13) domain and amplification in Pfplasmepsin 2 (Pfpm2) gene in Somalia. Methods: One-arm prospective studies were conducted to assess the clinical and parasitological responses to DHA/PPQ and AL at two sites in 2016 and 2017, respectively, using the standard WHO protocol. The patterns of molecular markers associated with artemisinin and PPQ resistance were investigated for the first time in Somalia. Results: A total of 339 patients were enrolled with 139 for AL and 200 for DHA/PPQ. With AL, no parasite recurrence was observed among patients treated at either site, corresponding to 100% clinical and parasitological responses. For DHA-PPQ, an adequate clinical and parasitological response rate > 97% was observed. All study patients on both treatments at both sites were parasite-free on day 3. Of the 138 samples with interpretable results for the polymorphism in Pfk13, only one (0.7%), from Bosaso, contained a non-synonymous mutation (R622I), which is not one of the known markers of artemisinin resistance. No Pfpm2 amplification was observed among the 135 samples with interpretable results. Conclusions: AL and DHA/PPQ were highly effective in the treatment of uncomplicated falciparum malaria, and there was no evidence of resistance to artemisinin or PPQ. These two combinations are thus relevant in the chemotherapeutic strategy for malaria control in Somalia.
|
|
| 22. |
- Warsame, Marian, et al.
(författare)
-
Pre-referral Rectal Artesunate Treatment by Community-Based Treatment Providers in Ghana, Guinea-Bissau, Tanzania, and Uganda (Study 18): A Cluster-Randomized Trial.
- 2016
-
Ingår i: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. - : Oxford University Press (OUP). - 1537-6591. ; 63:suppl 5
-
Tidskriftsartikel (refereegranskat)abstract
- If malaria patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate prior to hospital referral can prevent death and disability. The goal is to reduce death from malaria by having rectal artesunate treatment available and used. How best to do this remains unknown.Villages remote from a health facility were randomized to different community-based treatment providers trained to provide rectal artesunate in Ghana, Guinea-Bissau, Tanzania, and Uganda. Prereferral rectal artesunate treatment was provided in 272 villages: 109 through community-based health workers (CHWs), 112 via trained mothers (MUMs), 25 via trained traditional healers (THs), and 26 through trained community-chosen personnel (COMs); episodes eligible for rectal artesunate were established through regular household surveys of febrile illnesses recording symptoms eligible for prereferral treatment. Differences in treatment coverage with rectal artesunate in children aged <5 years in MUM vs CHW (standard-of-care) villages were assessed using the odds ratio (OR); the predictive probability of treatment was derived from a logistic regression analysis, adjusting for heterogeneity between clusters (villages) using random effects.Over 19 months, 54 013 children had 102 504 febrile episodes, of which 32% (31 817 episodes) had symptoms eligible for prereferral therapy; 14% (4460) children received treatment. Episodes with altered consciousness, coma, or convulsions constituted 36.6% of all episodes in treated children. The overall OR of treatment between MUM vs CHW villages, adjusting for country, was 1.84 (95% confidence interval [CI], 1.20-2.83; P = .005). Adjusting for heterogeneity, this translated into a 1.67 higher average probability of a child being treated in MUM vs CHW villages. Referral compliance was 81% and significantly higher with CHWs vs MUMs: 87% vs 82% (risk ratio [RR], 1.1 [95% CI, 1.0-1.1]; P < .0001). There were more deaths in the TH cluster than elsewhere (RR, 2.7 [95% CI, 1.4-5.6]; P = .0040).Prereferral episodes were almost one-third of all febrile episodes. More than one-third of patients treated had convulsions, altered consciousness, or coma. Mothers were effective in treating patients, and achieved higher coverage than other providers. Treatment access was low.ISRCTN58046240.
|
|
