Dataset Information

Plasmodium 18S Ribosomal RNA Biomarker Clearance After Food and Drug Administration-Approved Antimalarial Treatment in Controlled Human Malaria Infection Trials.

ABSTRACT:

Background

Sensitive molecular assays, such as quantitative reverse-transcription polymerase chain reaction (qRT-PCR) of Plasmodium 18S ribosomal RNA (rRNA), are increasingly the primary method of detecting infections in controlled human malaria infection (CHMI) trials. However, thick blood smears (TBSs) remain the main method for confirming clearance of parasites after curative treatment, in part owing to uncertainty regarding biomarker clearance rates.

Methods

For this analysis, 18S rRNA qRT-PCR data were compiled from 127 Plasmodium falciparum-infected participants treated with chloroquine or atovaquone-proguanil in 6 CHMI studies conducted in Seattle, Washington, over the past decade. A survival analysis approach was used to compare biomarker and TBS clearance times among studies. The effect of the parasite density at which treatment was initiated on clearance time was estimated using linear regression.

Results

The median time to biomarker clearance was 3 days (interquartile range, 3-5 days), while the median time to TBS clearance was 1 day (1-2 days). Time to biomarker clearance increased with the parasite density at which treatment was initiated. Parasite density did not have a significant effect on TBS clearance.

Conclusions

The Plasmodium 18S rRNA biomarker clears quickly and can be relied on to confirm the adequacy of Food and Drug Administration-approved treatments in CHMI studies at nonendemic sites.

SUBMITTER: Chavtur C

PROVIDER: S-EPMC10230565 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

<i>Plasmodium</i> 18S Ribosomal RNA Biomarker Clearance After Food and Drug Administration-Approved Antimalarial Treatment in Controlled Human Malaria Infection Trials.

Chavtur Chris C Staubus Weston J WJ Ho Mabel M Hergott Dianna E B DEB Seilie Annette M AM Healy Sara S Duffy Patrick P Jackson Lisa L Talley Angela A Kappe Stefan H I SHI Hoffman Stephen L SL Richie Thomas L TL Kublin James G JG Chang Ming M Murphy Sean C SC

Open forum infectious diseases 20230413 5

<h4>Background</h4>Sensitive molecular assays, such as quantitative reverse-transcription polymerase chain reaction (qRT-PCR) of <i>Plasmodium</i> 18S ribosomal RNA (rRNA), are increasingly the primary method of detecting infections in controlled human malaria infection (CHMI) trials. However, thick blood smears (TBSs) remain the main method for confirming clearance of parasites after curative treatment, in part owing to uncertainty regarding biomarker clearance rates.<h4>Methods</h4>For this an ...[more]

PMID: 37265668

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Project description:BackgroundArtefenomel (OZ439) is a novel synthetic trioxolane with improved pharmacokinetic properties compared with other antimalarial drugs with the artemisinin pharmacophore. Artefenomel has been generally well tolerated in volunteers at doses up to 1600 mg and is being developed as a partner drug in an antimalarial combination treatment. We investigated the efficacy, tolerability, and pharmacokinetics of artefenomel at different doses in patients with Plasmodium falciparum or Plasmodium vivax malaria.MethodsThis phase 2a exploratory, open-label trial was done at the Hospital for Tropical Diseases, Bangkok, and the Shoklo Malaria Research Unit in Thailand. Adult patients with acute, uncomplicated P falciparum or P vivax malaria received artefenomel in a single oral dose (200 mg, 400 mg, 800 mg, or 1200 mg). The first cohort received 800 mg. Testing of a new dose of artefenomel in a patient cohort was decided on after safety and efficacy assessment of the preceding cohort. The primary endpoint was the natural log parasite reduction per 24 h. Definitive oral treatment was given at 36 h. This trial is registered with ClinicalTrials.gov, number NCT01213966.FindingsBetween Oct 24, 2010, and May 25, 2012, 82 patients were enrolled (20 in each of the 200 mg, 400 mg, and 800 mg cohorts, and 21 in the 1200 mg cohort). One patient withdrew consent (before the administration of artefenomel) but there were no further dropouts. The parasite reduction rates per 24 h ranged from 0·90 to 1·88 for P falciparum, and 2·09 to 2·53 for P vivax. All doses were equally effective in both P falciparum and P vivax malaria, with median parasite clearance half-lives of 4·1 h (range 1·3-6·7) to 5·6 h (2·0-8·5) for P falciparum and 2·3 h (1·2-3·9) to 3·2 h (0·9-15·0) for P vivax. Maximum plasma concentrations, dose-proportional to 800 mg, occurred at 4 h (median). The estimated elimination half-life was 46-62 h. No serious drug-related adverse effects were reported; other adverse effects were generally mild and reversible, with the highest number in the 1200 mg cohort (17 [81%] patients with at least one adverse event). The most frequently reported adverse effect was an asymptomatic increase in plasma creatine phosphokinase concentration (200 mg, n=5; 400 mg, n=3; 800 mg, n=1; 1200 mg, n=3).InterpretationArtefenomel is a new synthetic antimalarial peroxide with a good safety profile that clears parasitaemia rapidly in both P falciparum and P vivax malaria. Its long half-life suggests a possible use in a single-dose treatment in combination with other drugs.FundingBill & Melinda Gates Foundation, Wellcome Trust, and UK Department for International Development.

Dataset Information

Plasmodium 18S Ribosomal RNA Biomarker Clearance After Food and Drug Administration-Approved Antimalarial Treatment in Controlled Human Malaria Infection Trials.

Background

Methods

Results

Conclusions

Publications

<i>Plasmodium</i> 18S Ribosomal RNA Biomarker Clearance After Food and Drug Administration-Approved Antimalarial Treatment in Controlled Human Malaria Infection Trials.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Plasmodium 18S Ribosomal RNA Biomarker Clearance After Food and Drug Administration-Approved Antimalarial Treatment in Controlled Human Malaria Infection Trials.

Background

Methods

Results

Conclusions

Publications

&lt;i&gt;Plasmodium&lt;/i&gt; 18S Ribosomal RNA Biomarker Clearance After Food and Drug Administration-Approved Antimalarial Treatment in Controlled Human Malaria Infection Trials.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

<i>Plasmodium</i> 18S Ribosomal RNA Biomarker Clearance After Food and Drug Administration-Approved Antimalarial Treatment in Controlled Human Malaria Infection Trials.