scholarly journals Efficacy of Three Antimalarial Regimens for Uncomplicated Plasmodium Falciparum Malaria in Cambodia, 2009 – 2011: A Randomized Control Trial

2021 ◽  
Author(s):  
Dysoley Lek ◽  
Agus Rachmat ◽  
Dustin Harrison ◽  
Geoffrey Chin ◽  
Suwanna Chaoratanakawee ◽  
...  
Keyword(s):  
Falciparum Malaria ◽  
Copy Number ◽  
Controlled Trial ◽  
Artemisinin Resistance ◽  
Uncomplicated Falciparum Malaria ◽  
Multi Drug Resistance ◽  
Directly Observed Therapy ◽  
Open Label ◽  
Northern Border

Abstract Background: Antimalarial resistance remains an important public health challenge in Cambodia. The effectiveness of three therapies for uncomplicated Falciparum malaria were evaluated in Oddar Meanchey province in Northern Cambodia from 2009 – 2011.Methods: In this randomized, open-label, parallel group controlled trial, 211 subjects at least 5 years old with uncomplicated Falciparum malaria were treated with directly observed therapy. Over 3 days, 63 received artesunate-mefloquine (AS/MQ), 77 received dihydroartemisinin-piperaquine (DHA/PPQ), and 71 received atovaquone-proguanil (ATQ/PG). Subjects were followed for 42 days or until recurrent parasitemia. Genotyping of msp1, msp2, and glurp among individual parasite isolates distinguished recrudescence from reinfection. Pfmdr1 copy number was measured by real-time PCR and half-maximal parasite inhibitory concentrations (IC50) was measured in vitro by 48-hour isotopic hypoxanthine incorporation assay.Results: The primary outcome of per-protocol PCR-adjusted efficacy at 42 days was analyzed for 190 (90.0%) of the enrolled subjects. PCR-adjusted efficacy (95% confidence interval) at 42 days was 80.6% (70.8 – 90.5%) for AS/MQ, 97.2% (93.3 – 100%) for DHA/PPQ, and 92.9% (86.1 – 99.6%) for ATQ/PG. On day 3, 59.3% remained parasitemic. At baseline, 46.9% had microscopic P. falciparum gametocytemia. Both recurrences in the DHA/PPQ arm lost Pfmdr1 copy number amplification at recrudescence. All four recurrences in the ATQ/PG arm were wild-type for cytochrome bc1. One subject withdrew from the ATQ/PG arm due to drug allergy.Conclusions: This previously unpublished study was conducted at the epicenter of substantial multi-drug resistance that emerged soon thereafter. Occurring early in the national transition from AS/MQ to DHA/PPQ, both DHA/PPQ and ATQ/PG had acceptable efficacy against uncomplicated falciparum malaria. However, efficacy of AS/MQ was only 80% with apparent mefloquine resistance based on elevated Pfmdr1 copy number and IC50. By 2009, there was already significant evidence of artemisinin resistance not previously reported at the Northern Cambodia-Thai border. This study suggests the basis for early development of significant DHA/PPQ failures within 3 years of introduction. Artemisinin resistance likely occurred on the Northern border concurrently with that reported along the Western border in Pailin.Trial Registration: This legacy trial was conducted prior to International Committee of Medical Journal Editors’ requirements for preregistration on ClinicalTrials.gov. The full protocol has been provided.

scholarly journals Clinical and in vitro resistance of Plasmodium falciparum to artesunate-amodiaquine in Cambodia

2020 ◽  
Author(s):  
Melissa Mairet-Khedim ◽  
Rithea Leang ◽  
Camille Marmai ◽  
Nimol Khim ◽  
Saorin Kim ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Markers ◽  
Falciparum Malaria ◽  
Artemisinin Resistance ◽  
Plasmodium Falciparum Malaria ◽  
Open Label ◽  
Parasite Survival ◽  
Adults And Children

Abstract Background Artesunate-amodiaquine is a potential therapy for uncomplicated malaria in Cambodia. Methods Between September 2016 and January 2017, artesunate-amodiaquine efficacy and safety were evaluated in a prospective, open-label, single-arm observational study at health centers in Mondulkiri, Pursat and Siem Reap Provinces, Cambodia. Adults and children with microscopically-confirmed Plasmodium falciparum malaria received oral artesunate-amodiaquine once daily for three days plus single-dose primaquine, with follow-up on Days 7, 14, 21 and 28. The primary outcome was Day-28 PCR-adjusted adequate clinical and parasitological response (ACPR). An amodiaquine parasite survival assay (AQSA) was developed and applied to whole genome sequencing results to evaluate potential amodiaquine resistance molecular markers. Results In 63 patients, Day-28 PCR-adjusted ACPR was 81.0% (95% confidence interval [CI], 68.9–88.7). Day 3 parasite positivity rate was 44.4% (28/63; 95%CI, 31.9–57.5). All 63 isolates had the K13(C580Y) marker for artemisinin resistance; 79.4% (50/63) had Pfpm2 amplification. The AQSA resistance phenotype (≥45% parasite survival) was expressed in 36.5% (23/63) of isolates and was significantly associated with treatment failure (P = 0.0020). Pfmdr1 mutant haplotypes were N86/184F/D1246 and Pfcrt was CVIET or CVIDT at positions 72–76. Additional Pfcrt mutations were not associated with amodiaquine resistance, but the G353V mutant allele was associated with ACPR compared to Pfmdr1 haplotypes harboring F1068L or S784L/R945P mutations (P = 0.030 and P = 0.0004, respectively). Conclusions For uncomplicated falciparum malaria in Cambodia, artesunate-amodiaquine had inadequate efficacy owing to amodiaquine-resistant P. falciparum. Amodiaquine resistance was not associated with previously identified molecular markers.

scholarly journals Evidence of Plasmodium falciparum Malaria Multidrug Resistance to Artemisinin and Piperaquine in Western Cambodia: Dihydroartemisinin-Piperaquine Open-Label Multicenter Clinical Assessment

2015 ◽  
Vol 59 (8) ◽  
pp. 4719-4726 ◽  
Author(s):  
Rithea Leang ◽  
Walter R. J. Taylor ◽  
Denis Mey Bouth ◽  
Lijiang Song ◽  
Joel Tarning ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Falciparum Malaria ◽  
Significant Risk ◽  
Artemisinin Resistance ◽  
Plasmodium Falciparum Malaria ◽  
Significant Risk Factor ◽  
Open Label ◽  
Content Type

ABSTRACTWestern Cambodia is recognized as the epicenter ofPlasmodium falciparummultidrug resistance. Recent reports of the efficacy of dihydroartemisinin (DHA)-piperaquine (PP), the latest of the artemisinin-based combination therapies (ACTs) recommended by the WHO, have prompted further investigations. The clinical efficacy of dihydroartemisinin-piperaquine in uncomplicated falciparum malaria was assessed in western and eastern Cambodia over 42 days. Day 7 plasma piperaquine concentrations were measured and day 0 isolates tested forin vitrosusceptibilities to piperaquine and mefloquine, polymorphisms in theK13gene, and the copy number of thePfmdr-1gene. A total of 425 patients were recruited in 2011 to 2013. The proportion of patients with recrudescent infections was significantly higher in western (15.4%) than in eastern (2.5%) Cambodia (P<10−3). Day 7 plasma PP concentrations and median 50% inhibitory concentrations (IC50) of PP were independent of treatment outcomes, in contrast to median mefloquine IC50, which were found to be lower for isolates from patients with recrudescent infections (18.7 versus 39.7 nM;P= 0.005). The most significant risk factor associated with DHA-PP treatment failure was infection by parasites carrying theK13mutant allele (odds ratio [OR], 17.5; 95% confidence interval [CI], 1 to 308;P= 0.04). Our data show evidence ofP. falciparumresistance to PP in western Cambodia, an area of widespread artemisinin resistance. New therapeutic strategies, such as the use of triple ACTs, are urgently needed and must be tested. (This study has been registered at the Australian New Zealand Clinical Trials Registry under registration no. ACTRN12614000344695.)

scholarly journals A Randomised Controlled Trial to Assess the Efficacy of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Falciparum Malaria in Peru

PLoS ONE ◽  
2007 ◽  
Vol 2 (10) ◽  
pp. e1101 ◽  
Author(s):  
Tanilu Grande ◽  
Andrea Bernasconi ◽  
Annette Erhart ◽  
Dioni Gamboa ◽  
Martin Casapia ◽  
...  
Keyword(s):  
Randomised Controlled Trial ◽  
Falciparum Malaria ◽  
Controlled Trial ◽  
Uncomplicated Falciparum Malaria ◽  
Randomised Controlled

scholarly journals Efficacy and safety of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria and prevalence of molecular markers associated with artemisinin and partner drug resistance in Uganda

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Chris Ebong ◽  
Asadu Sserwanga ◽  
Jane Frances Namuganga ◽  
James Kapisi ◽  
Arthur Mpimbaza ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Falciparum Malaria ◽  
Uncomplicated Malaria ◽  
Plasmodium Falciparum Malaria ◽  
Uncomplicated Falciparum Malaria ◽  
Pharmacokinetic Studies ◽  
Efficacy And Safety ◽  
Open Label ◽  
Serious Adverse Events ◽  
Line Therapy

Abstract Background In Uganda, artemether-lumefantrine (AL) is first-line therapy and dihydroartemisinin-piperaquine (DP) second-line therapy for the treatment of uncomplicated malaria. This study evaluated the efficacy and safety of AL and DP in the management of uncomplicated falciparum malaria and measured the prevalence of molecular markers of resistance in three sentinel sites in Uganda from 2018 to 2019. Methods This was a randomized, open-label, phase IV clinical trial. Children aged 6 months to 10 years with uncomplicated falciparum malaria were randomly assigned to treatment with AL or DP and followed for 28 and 42 days, respectively. Genotyping was used to distinguish recrudescence from new infection, and a Bayesian algorithm was used to assign each treatment failure a posterior probability of recrudescence. For monitoring resistance, Pfk13 and Pfmdr1 genes were Sanger sequenced and plasmepsin-2 copy number was assessed by qPCR. Results There were no early treatment failures. The uncorrected 28-day cumulative efficacy of AL ranged from 41.2 to 71.2% and the PCR-corrected cumulative 28-day efficacy of AL ranged from 87.2 to 94.4%. The uncorrected 28-day cumulative efficacy of DP ranged from 95.8 to 97.9% and the PCR-corrected cumulative 28-day efficacy of DP ranged from 98.9 to 100%. The uncorrected 42-day efficacy of DP ranged from 73.5 to 87.4% and the PCR-corrected 42-day efficacy of DP ranged from 92.1 to 97.5%. There were no reported serious adverse events associated with any of the regimens. No resistance-associated mutations in the Pfk13 gene were found in the successfully sequenced samples. In the AL arm, the NFD haplotype (N86Y, Y184F, D1246Y) was the predominant Pfmdr1 haplotype, present in 78 of 127 (61%) and 76 of 110 (69%) of the day 0 and day of failure samples, respectively. All the day 0 samples in the DP arm had one copy of the plasmepsin-2 gene. Conclusions DP remains highly effective and safe for the treatment of uncomplicated malaria in Uganda. Recurrent infections with AL were common. In Busia and Arua, the 95% confidence interval for PCR-corrected AL efficacy fell below 90%. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended. Trial registration The trail was also registered with the ISRCTN registry with study Trial No. PACTR201811640750761

scholarly journals Efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine and prevalence of molecular markers associated with resistance, Guinea: an open-label two-arm randomized controlled trial

2020 ◽  
Author(s):  
Abdoul Habib Beavogui ◽  
Alioune Camara ◽  
Alexandre Delamou ◽  
Abdoulaye Doumbouya ◽  
Karifa Kourouma ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Molecular Markers ◽  
Treatment Failure ◽  
Uncomplicated Malaria ◽  
Controlled Trial ◽  
Artemisinin Resistance ◽  
Efficacy And Safety ◽  
Open Label ◽  
Randomized Controlled ◽  
Kaplan Meier

Abstract ​ Background: Antimalarial resistance is a threat to recent gains in malaria control. This study aimed to assess the efficacy and safety of artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) in the management of uncomplicated malaria and to measure the prevalence of molecular markers of resistance of Plasmodium falciparum in sentinel sites in Maferinyah and Labé Health Districts in Guinea in 2016. Methods: This was a two-arm randomized controlled trial of the efficacy of AL and ASAQ among children aged 6-59 months with uncomplicated P. falciparum malaria in two sites. Children were followed for 28 days to assess clinical and parasitological response. The primary outcome was the Kaplan-Meier estimate of Day 28 (D28) efficacy after correction by microsatellite-genotyping. Pre-treatment (D0) and day of failure samples were assayed for molecular markers of resistance in the pfk13 and pfmdr1 genes. Results: A total of 421 participants were included with 211 participants in the Maferinyah site and 210 in Labé. No early treatment failure was observed in any study arms. However, 22 (5.3%) participants developed a late treatment failure (8 in the ASAQ arm and 14 in the AL arm), which were further classified as 2 recrudescences and 20 reinfections. The Kaplan-Meier estimate of the corrected efficacy at D28 was 100% for both AL and ASAQ in Maferinyah site and 99% (95% Confidence Interval: 97.2-100%) for ASAQ and 99% (97.1-100%) for AL in Labé. The majority of successfully analyzed D0 (98%, 380/389) and all day of failure (100%, 22/22) samples were wild type for pfk13 . All 9 observed pfk13 mutations were polymorphisms not associated with artemisinin resistance. The NFD haplotype was the predominant haplotype in both D0 (197/362, 54%) and day of failure samples (11/18, 61%) successfully analyzed for pfmdr1 . Vomiting was the most common observed side effect (14%) across all arms. Conclusions: This study observed high efficacy and safety of both ASAQ and AL in Guinea, providing evidence for their continued use to treat uncomplicated malaria. Continued monitoring of ACT efficacy and safety and molecular makers of resistance in Guinea is important to detect emergence of parasite resistance and to inform evidence-based malaria treatment policies.

scholarly journals A randomized open label trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis.

2019 ◽  
Vol 4 ◽  
pp. 8 ◽  
Author(s):  
Nguyen Thi Thuy Ngan ◽  
Nguyen Thi Hoang Mai ◽  
Nguyen Le Nhu Tung ◽  
Nguyen Phu Huong Lan ◽  
Luong Thi Hue Tai ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Treatment Guidelines ◽  
Controlled Trial ◽  
Safety Data ◽  
Open Label ◽  
Receptor Modulator ◽  
Open Label Trial ◽  
Early Fungicidal Activity

Background: Cryptococcal meningitis is a leading cause of death in HIV-infected patients. International treatment guidelines recommend induction therapy with amphotericin B and flucytosine. This antifungal combination is most effective, but unfortunately flucytosine is expensive and unavailable where the burden of disease is greatest. Where unavailable, guidelines recommend treatment with amphotericin and fluconazole, but this is less effective, with mortality rates of 40-50%. Faster rates of clearance of yeast from cerebrospinal fluid (CSF) are associated with better outcomes - improving the potency of antifungal therapy is likely to be an effective strategy to improve survival. Tamoxifen, a selective estrogen receptor modulator used to treat breast cancer, has anti-cryptococcal activity, appearing synergistic when combined in vitro with amphotericin, and fungicidal when combined with fluconazole. It is concentrated in the brain and macrophages, off-patent, cheap and widely available. We designed a randomized trial to deliver initial efficacy and safety data for tamoxifen combined with amphotericin and fluconazole. Method: A phase II, open-label, randomized (1:1) controlled trial of tamoxifen (300mg/day) combined with amphotericin (1mg/kg/day) and fluconazole (800mg/day) for the first 2 weeks therapy for HIV infected or uninfected adults with cryptococcal meningitis. The study recruits at Cho Ray Hospital and the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. The primary end point is Early Fungicidal Activity (EFA-the rate of yeast clearance from CSF), over the first two weeks of treatment. 50 patients will be recruited providing ≈80% and 90% power to detect a difference in the EFA of -0.11 or -0.13 log10CFU/ml/day, respectively. Discussion: The results of the study will inform the decision to proceed to a larger trial powered to mortality. The size of effect detectable has previously been associated with reduced mortality from this devastating disease. Particular side effects of interest include QT prolongation. Trial registration: Clinicaltrials.gov NCT03112031 (11/04/2017)

scholarly journals Atovaquone-Proguanil in Combination With Artesunate to Treat Multidrug-Resistant P. falciparum Malaria in Cambodia: An Open-Label Randomized Trial

2019 ◽  
Vol 6 (9) ◽  
Author(s):  
Mariusz Wojnarski ◽  
Chanthap Lon ◽  
Pattaraporn Vanachayangkul ◽  
Panita Gosi ◽  
Somethy Sok ◽  
...  
Keyword(s):  
Low Dose ◽  
Ex Vivo ◽  
Artemisinin Combination Therapy ◽  
Resistance Mutation ◽  
Artemisinin Resistance ◽  
Multidrug Resistant ◽  
Fixed Dose ◽  
Resistance Mutations ◽  
Open Label

Abstract Background Recent artemisinin-combination therapy failures in Cambodia prompted a search for alternatives. Atovaquone-proguanil (AP), a safe, effective treatment for multidrug-resistant Plasmodium falciparum (P.f.), previously demonstrated additive effects in combination with artesunate (AS). Methods Patients with P.f. or mixed-species infection (n = 205) in Anlong Veng (AV; n = 157) and Kratie (KT; n = 48), Cambodia, were randomized open-label 1:1 to a fixed-dose 3-day AP regimen +/-3 days of co-administered artesunate (ASAP). Single low-dose primaquine (PQ, 15 mg) was given on day 1 to prevent gametocyte-mediated transmission. Results Polymerase chain reaction–adjusted adequate clinical and parasitological response at 42 days was 90% for AP (95% confidence interval [CI], 82%–95%) and 92% for ASAP (95% CI, 83%–96%; P = .73). The median parasite clearance time was 72 hours for ASAP in AV vs 56 hours in KT (P &lt; .001) and was no different than AP alone. At 1 week postprimaquine, 7% of the ASAP group carried microscopic gametocytes vs 29% for AP alone (P = .0001). Nearly all P.f. isolates had C580Y K13 propeller artemisinin resistance mutations (AV 99%; KT 88%). Only 1 of 14 treatment failures carried the cytochrome bc1 (Pfcytb) atovaquone resistance mutation, which was not present at baseline. P.f. isolates remained atovaquone sensitive in vitro but cycloguanil resistant, with a triple P.f. dihydrofolate reductase mutation. Conclusions Atovaquone-proguanil remained marginally effective in Cambodia (≥90%) with minimal Pfcytb mutations observed. Treatment failures in the presence of ex vivo atovaquone sensitivity and adequate plasma levels may be attributable to cycloguanil and/or artemisinin resistance. Artesunate co-administration provided little additional blood-stage efficacy but reduced post-treatment gametocyte carriage in combination with AP beyond single low-dose primaquine.

Sign in / Sign up

Export Citation Format

Share Document