Browsing by Author "Tuntipaiboontana R."

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    Clinical antiviral efficacy of favipiravir in early COVID-19 (PLATCOV): an open-label, randomised, controlled, adaptive platform trial
    (2024-12-01) Luvira V.; Schilling W.H.K.; Jittamala P.; Watson J.A.; Boyd S.; Siripoon T.; Ngamprasertchai T.; Almeida P.J.; Ekkapongpisit M.; Cruz C.; Callery J.J.; Singh S.; Tuntipaiboontana R.; Kruabkontho V.; Ngernseng T.; Tubprasert J.; Abdad M.Y.; Keayarsa S.; Madmanee W.; Aguiar R.S.; Santos F.M.; Hanboonkunupakarn P.; Hanboonkunupakarn B.; Poovorawan K.; Imwong M.; Taylor W.R.J.; Chotivanich V.; Chotivanich K.; Pukrittayakamee S.; Dondorp A.M.; Day N.P.J.; Teixeira M.M.; Piyaphanee W.; Phumratanaprapin W.; White N.J.; Luvira V.; Mahidol University
    Brief summary: In early symptomatic COVID-19 treatment, high dose oral favipiravir did not accelerate viral clearance. Background: Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive. Favipiravir has been recommended for the treatment of COVID-19 in some countries. Methods: In a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomised to one of ten treatment arms including high dose oral favipiravir (3.6g on day 0 followed by 1.6g daily to complete 7 days treatment) or no study drug. The primary outcome was the rate of viral clearance (derived under a linear mixed-effects model from the daily log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 8 days [18 swabs per patient]), assessed in a modified intention-to-treat population (mITT). The safety population included all patients who received at least one dose of the allocated intervention. This ongoing adaptive platform trial was registered at ClinicalTrials.gov (NCT05041907) on 13/09/2021. Results: In the final analysis, the mITT population contained data from 114 patients randomised to favipiravir and 126 patients randomised concurrently to no study drug. Under the linear mixed-effects model fitted to all oropharyngeal viral density estimates in the first 8 days from randomisation (4,318 swabs), there was no difference in the rate of viral clearance between patients given favipiravir and patients receiving no study drug; a -1% (95% credible interval: -14 to 14%) difference. High dose favipiravir was well-tolerated. Interpretation: Favipiravir does not accelerate viral clearance in early symptomatic COVID-19. The viral clearance rate estimated from quantitative measurements of oropharyngeal eluate viral densities assesses the antiviral efficacy of drugs in vivo with comparatively few studied patients.
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    Clinical Antiviral Efficacy of Remdesivir in Coronavirus Disease 2019: An Open-Label, Randomized Controlled Adaptive Platform Trial (PLATCOV)
    (2023-11-11) Jittamala P.; Schilling W.H.K.; Watson J.A.; Luvira V.; Siripoon T.; Ngamprasertchai T.; Almeida P.J.; Ekkapongpisit M.; Cruz C.; Callery J.J.; Boyd S.; Anunsittichai O.; Hongsuwan M.; Singhaboot Y.; Pagornrat W.; Tuntipaiboontana R.; Kruabkontho V.; Ngernseng T.; Tubprasert J.; Abdad M.Y.; Keayarsa S.; Madmanee W.; Aguiar R.S.; Santos F.M.; Batty E.M.; Hanboonkunupakarn P.; Hanboonkunupakarn B.; Sookprome S.; Poovorawan K.; Imwong M.; Taylor W.R.J.; Chotivanich V.; Sangketchon C.; Ruksakul W.; Chotivanich K.; Pukrittayakamee S.; Dondorp A.M.; Day N.P.J.; Teixeira M.M.; Piyaphanee W.; Phumratanaprapin W.; White N.J.; Mahidol University
    BACKGROUND: Uncertainty over the therapeutic benefit of parenteral remdesivir in coronavirus disease 2019 (COVID-19) has resulted in varying treatment guidelines. METHODS: In a multicenter open-label, controlled, adaptive, pharmacometric platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to 1 of 8 treatment arms including intravenous remdesivir (200 mg followed by 100 mg daily for 5 days) or no study drug. The primary outcome was the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance (estimated under a linear model fit to the daily log10 viral densities, days 0-7) in standardized duplicate oropharyngeal swab eluates, in a modified intention-to-treat population. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907). RESULTS: The 2 study arms enrolled 131 patients (remdesivir n = 67, no study drug n = 64) and estimated viral clearance rates from a median of 18 swab samples per patient (a total of 2356 quantitative polymerase chain reactions). Under the linear model, compared with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated viral clearance by 42% (95% credible interval, 18%-73%). CONCLUSIONS: Parenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Pharmacometric assessment of therapeutics using the method described can determine in vivo clinical antiviral efficacy rapidly and efficiently.
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    Limited Polymorphism in the Dihydrofolate Reductase (dhfr) and dihydropteroate synthase genes (dhps) of Plasmodium knowlesi isolate from Thailand
    (2023-12-01) Sangsri R.; Choowongkomon K.; Tuntipaiboontana R.; Sugaram R.; Boondej P.; Sudathip P.; Dondorp A.M.; Imwong M.; Mahidol University
    Background: The 2022 malaria WHO reported around 4000 P. knowlesi infections in the South-East Asia region. In the same period, 72 positive cases were reported by the Department of Disease Control in Thailand, suggesting a persistent infection. Little is known about dihydrofolate reductase (pkdhfr) and dihydropteroate synthase (pkdhps), putative antimalarial resistance markers for P. knowlesi. The relevant amplification and sequencing protocol are presently unavailable. In this study, we developed a protocol for amplifying and evaluating pkdhps mutations. The haplotype pattern of pkdhfr–pkdhps in Thai isolates was analyzed, and the effects of these pkdhps mutations were predicted by using a computer program. Methods: Pkdhps were amplified and sequenced from 28 P. knowlesi samples collected in 2008 and 2020 from nine provinces across Thailand. Combining pkdhfr sequencing data from previous work with pkdhps data to analyze polymorphisms of pkdhfr and pkdhps haplotype. Protein modeling and molecular docking were constructed using two inhibitors, sulfadoxine and sulfamethoxazole, and further details were obtained through analyses of protein–ligand interactions by using the Genetic Optimisation for Ligand Docking program. A phylogenetic tree cluster analysis was reconstructed to compare the P. knowlesi Malaysia isolates. Results: Five nonsynonymous mutations in the pkdhps were detected outside the equivalence of the binding pocket sites to sulfadoxine and sulfamethoxazole, which are at N391S, E421G, I425R, A449S, and N517S. Based on the modeling and molecular docking analyses, the N391S and N517S mutations located close to the enzyme-binding pocket demonstrated a different docking score and protein–ligand interaction in loop 2 of the enzyme. These findings indicated that it was less likely to induce drug resistance. Of the four haplotypes of pkdhfr–pkdhps, the most common one is the R34L pkdhfr mutation and the pkdhps quadruple mutation (GRSS) at E421G, I425R, A449S, and N517S, which were observed in P. knowlesi in southern Thailand (53.57%). Based on the results of neighbor-joining analysis for pkdhfr and pkdhps, the samples isolated from eastern Thailand displayed a close relationship with Cambodia isolates, while southern Thailand isolates showed a long branch separated from the Malaysian isolates. Conclusions: A new PCR protocol amplification and evaluation of dihydropteroate synthase mutations in Knowlesi (pkdhps) has been developed. The most prevalent pkdhfr-pkdhps haplotypes (53.57%) in southern Thailand are R34L pkdhfr mutation and pkdhps quadruple mutation. Further investigation requires additional phenotypic data from clinical isolates, transgenic lines expressing mutant alleles, or recombinant proteins.
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    Temporal changes in SARS-CoV-2 clearance kinetics and the optimal design of antiviral pharmacodynamic studies: an individual patient data meta-analysis of a randomised, controlled, adaptive platform study (PLATCOV)
    (2024-01-01) Wongnak P.; Schilling W.H.K.; Jittamala P.; Boyd S.; Luvira V.; Siripoon T.; Ngamprasertchai T.; Batty E.M.; Singh S.; Kouhathong J.; Pagornrat W.; Khanthagan P.; Hanboonkunupakarn B.; Poovorawan K.; Mayxay M.; Chotivanich K.; Imwong M.; Pukrittayakamee S.; Ashley E.A.; Dondorp A.M.; Day N.P.J.; Teixeira M.M.; Piyaphanee W.; Phumratanaprapin W.; White N.J.; Watson J.A.; Callery J.; Cruz C.; Taylor W.; Thaipadungpanit J.; Ekkapongpisit M.; Kruabkontho V.; Ngernseng T.; Tubprasert J.; Abdad M.; Keayarsa S.; Anunsittichai O.; Hongsuwan M.; Singhaboot Y.; Madmanee W.; Tuntipaiboontana R.; Promsongsil A.; Saroj M.; Suwannasin K.; Beer E.; Asawasriworanan T.; Blacksell S.; Panapipat S.; Waithira N.; Tarning J.; Tanglakmankhong N.; Almeida P.J.; Aguiar R.S.; Ascencao F.; Esper L.; Vongsouvath M.; Phommasone K.; Dubot-Pérès A.; Vidhamaly S.; Chingsanoon A.; Bisayher S.; Chommanam D.; Evans T.; Vidhamaly V.; Boutthasavong L.; Vongphachanh S.; Potaporn M.; Srisubat A.; Loharjun B.; Beg M.A.; Kazi A.M.; Qamar F.; Ghanchi N.; Mahmood S.F.; Hanboonkunupakarn P.; Sookprome S.; Chotivanich V.; Ruksakul W.; Sangketchon C.; Wongnak P.; Mahidol University
    Background: Effective antiviral drugs prevent hospitalisation and death from COVID-19. Antiviral efficacy can be efficiently assessed in vivo by measuring rates of SARS-CoV-2 clearance estimated from serial viral genome densities quantitated in nasopharyngeal or oropharyngeal swab eluates. We conducted an individual patient data meta-analysis of unblinded arms in the PLATCOV platform trial to characterise changes in viral clearance kinetics and infer optimal design and interpretation of antiviral pharmacometric evaluations. Methods: Serial viral density data were analysed from symptomatic, previously healthy, adult patients (within 4 days of symptom onset) enrolled in a large multicentre, randomised, adaptive, pharmacodynamic, platform trial (PLATCOV) comparing antiviral interventions for SARS-CoV-2. Viral clearance rates over 1 week were estimated under a hierarchical Bayesian linear model with B-splines used to characterise temporal changes in enrolment viral densities and clearance rates. Bootstrap re-sampling was used to assess the optimal duration of follow-up for pharmacometric assessment, where optimal was defined as maximising the expected Z score when comparing effective antivirals with no treatment. PLATCOV is registered at ClinicalTrials.gov, NCT05041907. Findings: Between Sept 29, 2021, and Oct 20, 2023, 1262 patients were randomly assigned in the PLATCOV trial. Unblinded data were available from 800 patients (who provided 16 818 oropharyngeal viral quantitative PCR [qPCR] measurements), of whom 504 (63%) were female. 783 (98%) patients had received at least one vaccine dose and 703 (88%) were fully vaccinated. SARS-CoV-2 viral clearance was biphasic (bi-exponential). The first phase (α) was accelerated by effective interventions. For all the effective interventions studied, maximum discriminative power (maximum expected Z score) was obtained when evaluating serial data from the first 5 days after enrolment. Over the 2-year period studied, median viral clearance half-lives estimated over 7 days shortened from 16·6 h (IQR 15·3 to 18·2) in September, 2021, to 9·2 h (8·0 to 10·6) in October, 2023, in patients receiving no antiviral drugs, equivalent to a relative reduction of 44% (95% credible interval [CrI] 19 to 64). A parallel reduction in viral clearance half-lives over time was observed in patients receiving antiviral drugs. For example, in the 158 patients assigned to ritonavir-boosted nirmatrelvir (3380 qPCR measurements), the median viral clearance half-life reduced from 6·4 h (IQR 5·7 to 7·3) in June, 2022, to 4·8 h (4·2 to 5·5) in October, 2023, a relative reduction of 26% (95% CrI –4 to 42). Interpretation: SARS-CoV-2 viral clearance kinetics in symptomatic, vaccinated individuals accelerated substantially over 2 years of the pandemic, necessitating a change to how new SARS-CoV-2 antivirals are compared (ie, shortening the period of pharmacodynamic assessment). As of writing (October, 2023), antiviral efficacy in COVID-19 can be efficiently assessed in vivo using serial qPCRs from duplicate oropharyngeal swab eluates taken daily for 5 days after drug administration. Funding: Wellcome Trust.