Use of population pharmacokinetic‐pharmacodynamic modelling to inform antimalarial dose optimization in infants

Infants bear a significant malaria burden but are usually excluded from participating in early dose optimization studies that inform dosing regimens of antimalarial therapy. Unlike older children, infants' exclusion from early‐phase trials has resulted in limited evidence to guide accurate dosing of antimalarial treatment for uncomplicated malaria or malaria‐preventive treatment in this vulnerable population. Subsequently, doses used in infants are often extrapolated from older children or adults, with the potential for under‐ or overdosing. Population pharmacokinetic‐pharmacodynamic (PK‐PD) modelling, a quantitative methodology that applies mathematical and statistical techniques, can aid the design of clinical studies in infants that collect sparse pharmacokinetic data as well as support the analysis of such data to derive optimized antimalarial dosing in this complex and at‐risk yet understudied subpopulation. In this review, we reflect on what PK‐PD modelling can do in programmatic settings of most malaria‐endemic areas and how it can be used to inform antimalarial dose optimization for preventive and curative treatment of uncomplicated malaria in infants. We outline key developmental physiological changes that affect drug exposure in early life, the challenges of conducting dose optimization studies in infants, and examples of how PK‐PD modelling has previously informed antimalarial dose optimization in this subgroup. Additionally, we discuss the limitations and gaps of PK‐PD modelling when used for dose optimization in infants. To utilize modelling well, there is a need to generate useful, sparse, PK and PD data in this subpopulation to inform antimalarial optimal dosing in infancy

Impact of Dolutegravir-Based Antiretroviral Therapy on Piperaquine Exposure following Dihydroartemisinin-Piperaquine Intermittent Preventive Treatment of Malaria in Pregnant Women Living with HIV.

Dihydroartemisinin-piperaquine, an artemisinin-based combination therapy, has been identified as a promising agent for intermittent preventive treatment of malaria in pregnancy. However, in pregnant women living with HIV (PLWH), efavirenz-based antiretroviral therapy (ART) significantly reduces the plasma exposure of piperaquine. In an open-label, nonrandomized, fixed-sequence, pharmacokinetic study, we compared piperaquine plasma concentrations in 13 pregnant women during a 3-day treatment course of dihydroartemisinin-piperaquine when coadministered with efavirenz-based versus dolutegravir-based ART in the second or third trimester of pregnancy. Piperaquine concentrations were measured over a 28-day period, while on efavirenz-based ART and after switching to dolutegravir-based ART. Noncompartmental analysis was performed, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were generated to compare piperaquine pharmacokinetic parameters between these two treatment periods. Compared with efavirenz-based ART, coadministration of dihydroartemisinin-piperaquine and dolutegravir-based ART resulted in a 57% higher overall piperaquine exposure (area under the concentration-time curve from 0 to 672 h [AUC ]) (GMR, 1.57; 90% CI, 1.28 to 1.93). Piperaquine's day 7 concentrations were also 63% higher (GMR, 1.63; 90% CI, 1.29 to 2.11), while day 28 concentrations were nearly three times higher (GMR, 2.96; 90% CI, 2.25 to 4.07). However, the maximum piperaquine concentration ( ) remained similar (GMR, 1.09; 90% CI, 0.79 to 1.49). Dihydroartemisinin-piperaquine was well tolerated, with no medication-related serious adverse events observed in this small study. Compared with efavirenz-based ART, a known inducer of piperaquine metabolism, dolutegravir-based ART resulted in increased overall piperaquine exposure with pharmacokinetic parameter values that were similar to those published previously for pregnant and nonpregnant women. Our findings suggest that the efficacy of dihydroartemisinin-piperaquine will be retained in pregnant women on dolutegravir

Impact of Dolutegravir-Based Antiretroviral Therapy on Piperaquine Exposure following Dihydroartemisinin-Piperaquine Intermittent Preventive Treatment of Malaria in Pregnant Women Living with HIV

Dihydroartemisinin-piperaquine, an artemisinin-based combination therapy, has been identified as a promising agent for intermittent preventive treatment of malaria in pregnancy. However, in pregnant women living with HIV (PLWH), efavirenz-based antiretroviral therapy (ART) significantly reduces the plasma exposure of piperaquine. In an open-label, nonrandomized, fixed-sequence, pharmacokinetic study, we compared piperaquine plasma concentrations in 13 pregnant women during a 3-day treatment course of dihydroartemisinin-piperaquine when coadministered with efavirenz-based versus dolutegravir-based ART in the second or third trimester of pregnancy. Piperaquine concentrations were measured over a 28-day period, while on efavirenz-based ART and after switching to dolutegravir-based ART. Noncompartmental analysis was performed, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were generated to compare piperaquine pharmacokinetic parameters between these two treatment periods. Compared with efavirenz-based ART, coadministration of dihydroartemisinin-piperaquine and dolutegravir-based ART resulted in a 57% higher overall piperaquine exposure (area under the concentration-time curve from 0 to 672 h [AUC0-672 h]) (GMR, 1.57; 90% CI, 1.28 to 1.93). Piperaquine's day 7 concentrations were also 63% higher (GMR, 1.63; 90% CI, 1.29 to 2.11), while day 28 concentrations were nearly three times higher (GMR, 2.96; 90% CI, 2.25 to 4.07). However, the maximum piperaquine concentration (Cmax) remained similar (GMR, 1.09; 90% CI, 0.79 to 1.49). Dihydroartemisinin-piperaquine was well tolerated, with no medication-related serious adverse events observed in this small study. Compared with efavirenz-based ART, a known inducer of piperaquine metabolism, dolutegravir-based ART resulted in increased overall piperaquine exposure with pharmacokinetic parameter values that were similar to those published previously for pregnant and nonpregnant women. Our findings suggest that the efficacy of dihydroartemisinin-piperaquine will be retained in pregnant women on dolutegravir. (The study was registered on PACTR.samrc.ac.za [PACTR201910580840196].). Erratum: In Fig.2 and Fig. S1, the first value on the y axis should read as “1” instead of “0.

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Pharmacokinetics of Piperaquine and Safety Profile of Dihydroartemisinin-Piperaquine Coadministered with Antiretroviral Therapy in Malaria-Uninfected HIV-Positive Malawian Adults.

There are limited data on the pharmacokinetic and safety profiles of dihydroartemisinin-piperaquine (DHA-PQ) among human immunodeficiency virus-infected (HIV-positive [HIV+]) individuals taking antiretroviral therapy (ART). In a two-step (parallel-group) pharmacokinetic trial with intensive blood sampling, we compared the area under the concentration-time curve from days 0 to 28 (AUC0-28 days) and the safety outcomes of piperaquine among malaria-uninfected HIV+ adults. In step 1, half the adult dose of DHA-PQ was administered for 3 days as an initial safety check to four groups (n = 6/group) of HIV+ adults (age ≥18 years): (i) antiretroviral-naive individuals, (ii) individuals on nevirapine-based ART, (iii) individuals on efavirenz-based ART, and (iv) individuals on ritonavir-boosted lopinavir-based ART. In step 2, a full adult treatment course of DHA-PQ was administered to a different cohort of participants in three groups: (i) antiretroviral-naive individuals, (ii) individuals on efavirenz-based ART, and (iii) individuals on nevirapine-based ART (n = 10 to 15/group). The ritonavir-boosted lopinavir-based ART group was dropped in step 2 due to the limited number of participants who were on this second-line ART and were eligible for recruitment. Piperaquine's AUC0-28 days in both steps was 43% lower among participants on efavirenz-based ART than among ART-naive participants. There were no significant differences in AUC0-28 days between the other ART groups and the ART-naive group in each of the two steps. Furthermore, no differences in treatment-emergent clinical and laboratory adverse events were observed across the groups in steps 1 and 2. Although it was well tolerated at the half and full standard adult treatment courses, the efavirenz-based antiretroviral regimen was associated with reduced piperaquine exposure, which may compromise dihydroartemisinin-piperaquine's effectiveness in programmatic settings. (The clinical trials presented in this study have been registered at the WHO's International Clinical Trials Registry Platform under ID numbers PACTR2010030001871293 and PACTR2010030001971409.)